Aryl hydrocarbon receptor: The master regulator of immune responses in allergic diseases

Abstract

The aryl hydrocarbon receptor (AhR) is a widely studied ligand-activated cytosolic transcriptional factor that has been associated with the initiation and progression of various diseases, including autoimmune diseases, cancers, metabolic syndromes, and allergies. Generally, AhR responds and binds to environmental toxins/ligands, dietary ligands, and allergens to regulate toxicological, biological, cellular responses. In a canonical signaling manner, activation of AhR is responsible for the increase in cytochrome P450 enzymes which help individuals to degrade and metabolize these environmental toxins and ligands. However, canonical signaling cannot be applied to all the effects mediated by AhR. Recent findings indicate that activation of AhR signaling also interacts with some non-canonical factors like Kruppel-like-factor-6 (KLF6) or estrogen-receptor-alpha (Erα) to affect the expression of downstream genes. Meanwhile, enormous research has been conducted to evaluate the effect of AhR signaling on innate and adaptive immunity. It has been shown that AhR exerts numerous effects on mast cells, B cells, macrophages, antigen-presenting cells (APCs), Th1/Th2 cell balance, Th17, and regulatory T cells, thus, playing a significant role in allergens-induced diseases. This review discussed how AhR mediates immune responses in allergic diseases. Meanwhile, we believe that understanding the role of AhR in immune responses will enhance our knowledge of AhR-mediated immune regulation in allergic diseases. Also, it will help researchers to understand the role of AhR in regulating immune responses in autoimmune diseases, cancers, metabolic syndromes, and infectious diseases.

Full text

Aryl hydrocarbon receptor: The
master regulator of immune
responses in allergic diseases
Farooq Riaz
1
, Fan Pan
1
*and Ping Wei
2
*
1
Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences (CAS),
Shenzhen, China,
2
Department of Otolaryngology, Children’s Hospital of Chongqing Medical
University, National Clinical Research Center for Child Health and Disorders, Ministry of Education
Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Translational
Medical Research in Cognitive Development and Learning and Memory Disorders,
Chongqing, China
The aryl hydrocarbon receptor (AhR) is a widely studied ligand-activated
cytosolic transcriptional factor that has been associated with the initiation
and progression of various diseases, including autoimmune diseases, cancers,
metabolic syndromes, and allergies. Generally, AhR responds and binds to
environmental toxins/ligands, dietary ligands, and allergens to regulate
toxicological, biological, cellular responses. In a canonical signaling manner,
activation of AhR is responsible for the increase in cytochrome P450 enzymes
which help individuals to degrade and metabolize these environmental toxins
and ligands. However, canonical signaling cannot be applied to all the effects
mediated by AhR. Recent findings indicate that activation of AhR signaling also
interacts with some non-canonical factors like Kruppel-like-factor-6 (KLF6) or
estrogen-receptor-alpha (Era) to affect the expression of downstream genes.
Meanwhile, enormous research has been conducted to evaluate the effect of
AhR signaling on innate and adaptive immunity. It has been shown that AhR
exerts numerous effects on mast cells, B cells, macrophages, antigen-
presenting cells (APCs), Th1/Th2 cell balance, Th17, and regulatory T cells,
thus, playing a significant role in allergens-induced diseases. This review
discussed how AhR mediates immune responses in allergic diseases.
Meanwhile, we believe that understanding the role of AhR in immune
responses will enhance our knowledge of AhR-mediated immune regulation
in allergic diseases. Also, it will help researchers to understand the role of AhR in
regulating immune responses in autoimmune diseases, cancers, metabolic
syndromes, and infectious diseases.
KEYWORDS
aryl hydrocarbon receptor (AhR), allergy, innate immunity, adaptive immunity, T cell,
autoimmune disease
Frontiers in Immunology frontiersin.org01
OPEN ACCESS
EDITED BY
Bo Zhang,
Huazhong University of Science and
Technology, China
REVIEWED BY
Huaqi Guo,
Shanghai Jiao Tong University, China
Xue-Feng Bai,
The Ohio State University,
United States
Guangyong Peng,
Saint Louis University, United States
*CORRESPONDENCE
Ping Wei
weiweidoctor@sina.cn
Fan Pan
fan.pan@siat.ac.cn
SPECIALTY SECTION
This article was submitted to
Immunological Tolerance
and Regulation,
a section of the journal
Frontiers in Immunology
RECEIVED 29 September 2022
ACCEPTED 02 December 2022
PUBLISHED 19 December 2022
CITATION
Riaz F, Pan F and Wei P (2022) Aryl
hydrocarbon receptor: The master
regulator of immune responses in
allergic diseases.
Front. Immunol. 13:1057555.
doi: 10.3389/fimmu.2022.1057555
COPYRIGHT
© 2022 Riaz, Pan and Wei. This is an
open-access article distributed under
the terms of the Creative Commons
Attribution License (CC BY). The use,
distribution or reproduction in other
forums is permitted, provided the
original author(s) and the copyright
owner(s) are credited and that the
original publication in this journal is
cited, in accordance with accepted
academic practice. No use,
distribution or reproduction is
permitted which does not comply with
these terms.
TYPE Review
PUBLISHED 19 December 2022
DOI 10.3389/fimmu.2022.1057555

Introduction
The aryl hydrocarbon receptor (AhR) belongs to the PAS
(Per-ARNT-Sim), a superfamily of transcriptional factors widely
found in numerous tissues throughout the body (1,2). Genes
belonging to PAS domains, typically AhR, enhance the
environmental adaptations by sensing and detecting the
environmental signals, including the redox potential or oxygen
tension (HIF-1a,-2a, and -3a) and circadian rhythm (BMAL-1
and -2) (3). Besides, numerous chemicals and toxins, such as
polycyclic aromatic hydrocarbons (PAHs) and Polyhalogenated
aromatic hydrocarbons (PHAHs), affect the AhR-dependent
responses. Among these, 2,3,7,8- tetrachlorodibenzo-[p]-dioxin
(TCDD) is a PHAH toxin that is the most potent ligand for AhR
(4). Upon activation, AhR alters the immunotoxicological
outcomes and the transcription of AhR-targeted genes
cytochrome P450 1A1 and cytochrome P450 1B1 (5,6).
It was discussed that, upon activation, AhR regulates the
transcription of multiple genes by translocating from the
cytoplasm to the nucleus. However, recent studies imply that
numerous physiologic ligands, e.g., intestinal microbiota,
metabolites, and diet, interact with the host to influence AhR-
dependent transcription. Identification and characterization of
these natural ligands in AhR transgenic mice have demonstrated
their pivotal role in AhR signaling (7).
As a transcriptional factor, AhR cooperates with various
environmental factors, which act as agonists for AhR, and
participates in the disease progression (7–9). AhR sensing and
responding to environmental stimuli can play fundamental roles
in cellular developmental processes and immune regulation (10).
It has been well established that AhR plays a modulatory role in
mediating the innate and adaptive immune response to combat
various infectious diseases (11,12), metabolic diseases (13–15),
cancer (16,17), and allergic diseases (18,19). In the existing
manuscript, we will review the role of AhR on the immune cells
in response to environmental allergens.
Mode of action of AhR
AhR, a well-conserved protein, is ubiquitously expressed in
mammalian organs with flexible expression levels amongst
different tissues at different stages of life (20–22). Briefly, in an
inactive state, AhR is present within the cell cytosol in the form
of a protein complex. During activation after binding to its
ligands, such as an allergen or environmental toxin, AhR
undergoes conformational changes and translocates to the
nucleus. After translocation, AhR triggers the transcription of
numerous target genes through dioxin-responsive elements
(DREs) (23,24). Conversely, AhR prevents self-activation in a
negative feedback loop by degrading AhR through AhR
repressor (AhRR), which is a primary downstream target of
AhR (23,24). In addition to this canonical process, AhR also
influences biological processes in a non-canonical way. In a non-
canonical pathway, the cytoplasmic AhR complex is dissociated
from its ligand-receptor complex. It results in the release of
many biologically active molecules, including the c-SRC kinase,
which leads to the phosphorylation of numerous genes (25).
Remarkably, ligand-AhR acts as a facilitating protein during the
formation of the ubiquitin ligase complex, which eases the
degradation of steroid receptors, e.g., the central regulator of
adipogenesis peroxisome proliferator-activated receptor g
(PPARg)(26) or estrogen receptor (Era)(7,27), by enhancing
the substrate specificity. The AhR-canonical and non-canonical
signaling pathway is illustrated in Figure 1.
Before exposure to the ligand in the cytoplasm, inactive AhR
is present in the form of a protein complex that is comprised of
the hepatitis B virus X-associated protein (XAP2), the chaperone
heat-shock protein 90 (HSP-90), the co-chaperone p23 (p23),
and the c-SRC protein kinase (21,25,28–31). Hsp90 protein
keeps the right conformation of AhR for receptor bindings but
also averts the AhR translocation to the nucleus (32).
Conversely, the co-chaperone p23 is highly involved in
stabilizing the interaction and complex of AhR-Hsp90, while
the ARA9 elevates the AhR activation by properly folding AHR
in the cytoplasm (33,34).
Furthermore, HSP90 adjusts the AhR in the correct position
to provide a high affinity for its ligands (32), while AhR steady-
state cellular levels are maintained by AIP, which prevents AhR
ubiquitination and degradation (35). The release of AIP from the
complex exposes the nuclear signals of AhR. This leads to pivotal
conformational changes in AhR; thus, it may lead to the nuclear
translocation of AhR (36). On the other side, the nuclear
translocation of AhR is also dependent on the phosphorylation
of protein kinase C (37), establishing the fact that AhR is being
controlled through several mechanisms. Additionally, regulating
the nuclear translocation of AhR can be a potential therapeutic
target for the precise reorientation of non-canonical
AhR signaling.
During the activation of the canonical AhR signaling
pathway in the presence of agonists, the ARA9-AhR-HSP90-
p23 complex undergoes a conformational change which helps
the translocation of this complex to the nucleus via b-importins
(21,25,28–31). Several investigations suggest that XAP2
anchors the AhR complex in the cytoplasm. Other inquiries
contend that XAP2 restricts the interaction of b-importins with
nuclear localization signal. Importantly, prior to the
nucleocytoplasmicshuttling,thereleaseofXAP2fromthe
AhR complex is necessary (36,38–40).
Further studies conducted in HeLa cells indicated that
translocation of AhR to the nucleus could happen without
being dissociated from HSP90 (38). Though, it’sunclear
whether this finding can be generalized to various cell types or
other AhR agonists (41,42). Technically, AhR within the nucleus
undergoes conformational changes by heterodimerizing with the
Riaz et al. 10.3389/fimmu.2022.1057555
Frontiers in Immunology frontiersin.org02

AhR nuclear translocator (ARNT). Meanwhile, it also binds with
particular DNA sequences, known as xenobiotics- or dioxin-
response elements (XRE or DRE), to modulate the level of
specificgenes(29,43–46). These genes contain numerous
enzymes involved in xenobiotic metabolization, e.g., NAD(P)
H-quinone oxidoreductase, CYP1A1, CYP1A2, and
CYP1B1 (47).
In addition, AhR can control the expression of various genes
directly by interacting with specific DNA sequences or indirectly
by interacting with regulatory RNAs and transcription factors.
These AhR-mediated regulations of gene expressions are
generally achieved in an AhR-non-canonical signaling pathway
manner. Practically, 5’-TNGCGTG-3’is a DNA consensus motif
located in the AhR target gene responsible for the interaction of
AhR in the genomic regulatory regions. These DNA consensus
motifs are recognized as DRE or XRE (48). Besides interacting
with DREs or XREs, the AhR/ARNT complex also modulates the
expression of various genes by interacting with various
transcriptional factors. AhR exerts a significant effect during
the chromatin remodeling during the interaction of AhR with
chromatin-remodeling complexes, i.e., the steroid receptor
coactivator-1 (SRC-1) (49), SWI/SNF (50), and by relocating
the histone deacetylase (HDAC) complexes (51).
AhR has also been categorized to regulate the expression of a
variety of downstream target genes by its interaction with their
respective transcription factors, e.g., retinoblastoma protein
(Rb), the estrogen receptor and E2F, the retinoic acid receptor,
c-Maf, and NF-kB(52). AhR-dependent activity of these
transcription factors is involved in mediating the numerous
feedback loops which are extremely related to immune
FIGURE 1
Activation of the aryl hydrocarbon receptor (AhR) canonical and non-canonical signaling pathway. AhR is present in all cell types in the form of
a complex with Hsp90, ARA9, XAP2, p23 and c-SRC. Upon interaction with exogenous or endogenous ligands, AhR-complex undergoes
conformational changes and uses importin bfor the nucleocytoplasmic shuttling. In the AhR-canonical signaling pathway, AhR interacts with
ARNT and binds to the XRE to regulate gene expression. In the AhR-non-canonical signaling pathway, AhR binds to various other transcription
factors to regulate gene expression. AhR-aryl hydrocarbon receptor; ARNT-AhR nuclear translocator; AhRR-AhR repressor; CYP1A1, cytochrome P450
1A1; CYP1B1-cytochrome P450 1B1; c-SRC-proto-oncogene tyrosine-protein kinase Src; ARA9-immunophilin homolog ARA9; HSP90-heat shock
protein of 90 kDa; p23-prostaglandin E synthase 3; XAP2-hepatitis B virus X-associated protein 2; IDOI-indoleamine 2,3-dioxygenase 1;
TDO-tryptophan 2,3-dioxygenase; TF-transcription factor; KLF6-Krüppel-like factor6; RAR-retinoic acid receptor; ERa-oestrogen receptor-alpha;
Rb-retinoblastoma protein; SOCS2-suppressor of cytokine signaling 2; XRE-xenobiotic response element; DRE- Ub-ubiquitylation; P-
phosphorylation. The illustration is drawn by BioRender (biorender.com).
Riaz et al. 10.3389/fimmu.2022.1057555
Frontiers in Immunology frontiersin.org03

regulation. For instance, NF-kB elevates the AhR expression;
however, AhR can alternatively modulate the NF-kB signaling
(53–55).
Similarly, an alternative to canonical DREs, AhR can also be
associated with numerous other transcription factors, which can
help AhR to be directly recruited to the target DNA sequences.
For instance, dimerization of AhR with RelA and RelB can direct
the recruitment of AhR at the responding sites of NF-kB sites
(56,57) and with KLF6 (58). It suggests that non-canonical AhR
signaling leads to the AhR recruitment to various non-consensus
DNA elements. Strikingly, various ligands have been associated
with enhancing the interaction of AhR with multiple genes (59).
The recruitment of AhR at different target sites can subsequently
alter the biological and cellular processes, including the immune
responses in allergic diseases, cancers, and autoimmune diseases.
Allergic diseases
It is estimated that nearly 22% of the global population suffers
from allergic disorders. These include eczema, allergic asthma,
allergic rhinitis, drug or food allergic reactions, anaphylaxis, and
allergic conjunctivitis (60,61). Globally, allergic diseases are
touching epidemic proportions with a particular increase among
westerners. Since allergic diseases are highly associated with
inflammation, various studies suggest a close association of
allergic diseases with the onset of numerous complicated
diseases, particularly metabolic diseases (62), cancer (63), mental
disorders (64), stroke (65), and cardiovascular diseases (66).
Similarly, allergic rhinitis and asthma are related to the high risk
of obesity, insulin resistance, and blood sugar (67–70). These
studies suggest that the pathogenesis of allergic diseases also can
serve as an etiological factor for various other diseases. Therefore,
we must improve our knowledge about allergic diseases and the
impact of these allergic diseases on other associated diseases (71).
The current description of allergic diseases as abnormal
conditions principally initiated in an immunoglobulin E (IgE)-
dependent mechanisms is not well-applicable to all allergy patients
(72). Typically, in allergic individuals, binding of IgE with primary
allergens triggers allergic responses in ~50% of patients. In
comparison, other non-primary allergens trigger an allergic
reaction and activate various immune cells (73,74). Therefore, it
is necessary to determine the appropriate functions of immune cells
in allergic inflammatory responses, so we can develop innovative,
beneficial strategies to constrain allergic diseases.
Molecular mechanism of
allergic diseases
Significant development has been made in understanding
the intrinsic and structural biology of potential allergens and
environmental agents (75). Allergic inflammatory reactions are
specified through the assortment of the Th2-cell-dependent
signaling pathway. This Th2-cell pathway begins upon the
exposure of allergens and their uptake by the first line of
defense antigen-presenting cells (APCs). APCs display the
particular peptides/antigens to naïve T cells via MHC class II
receptor. Thereby. Naïve T cells are directed towards the Th2-
cell phenotype, which generally mediates the expression of
secretory cytokine via transcription factor GATA3 (GATA-
binding protein 3) (76). Meanwhile, Th1 phenotypic responses
are generalized by the secretion of cytokines, i.e., interferon-g
(IFNg) through the T-bet transcriptional factor. Overall, T cells
play a leading role during the development and advancement of
autoimmune, allergic, and cancerous diseases (Figure 2)(77).
Besides, it has been characterized that IgE binds to mast cells to
activate mast cell degranulation and contributes to presenting the
antigen to other immune cells. On the contrary, eosinophils yield
some pro-inflammatory cytokines that can activate bronchial
hyperreactivity and allergic inflammation (78,79). Meanwhile,
when APCs present potential antigens to naïve T cells via MHC-
II, T cells are activated. Activated T cells coordinately elevate the
secretion of a bunch of cytokines encoded by human chromosome
5q31–33. Briefly, activation of T cells encodes granulocyte/
macrophage colony-stimulating factor (GM-CSF) and interleukin-
3 (IL-3), IL-4, IL-5, IL-9, and IL-13 (80). These cytokines play
crucial roles during allergic inflammation.
The Th2/Th1 imbalance during allergic responses has been
established for more than two decades (81). However, recent
investigations have discovered regulatory T (Tregs) cells as an
additional crucial subset of CD4
+
T cells, which is essential in
mediating allergic disease (82). Increasing evidence from in-vivo
allergic mice models sturdily associate Tregs with the suppression of
allergen-specific responses and allergic inflammation (83). Moreover,
numerous studies also stated that Tregs regulate the Th2-cell-mediated
allergic responses by secreting various suppressive cytokines, including
transforming growth factor-b(TGFb) and IL-10, and urged that
allergic reactions are consequent of Th2/Treg imbalance (84).
As the prevalence and morbidity rate of allergies is growing
worldwide (85,86), it is necessary to develop and design new
treatment strategies that mask the symptoms of allergies and
reduce the basic allergic cascade during allergic inflammation.
As mentioned earlier, immune cell-mediated allergic responses
are gaining importance in the scientific community. However,
how immune cells mediate the immune responses to counter
environmental nonpathogenic antigens, which progress to
allergic reactions, is not well understood.
AhR in regulating immune responses
in allergic diseases
Striking evidence indicates the extensive role of IgE and
eosinophils in the pathogenesis of allergic inflammation and the
Riaz et al. 10.3389/fimmu.2022.1057555
Frontiers in Immunology frontiersin.org04

development of therapeutic strategies targeting IgE and
eosinophils (87). Nevertheless, the role of other immune cells
in allergic reactions hasn’t been investigated well. Meanwhile,
theroleofAhRinregulatingtheinflammatory effects of
environmental pollutants and allergens makes it an attractive
target for achieving therapy against allergic diseases (88). In
response to potential allergens and AhR ligands, the expression
of AhR and the downstream signaling pathway exert various
roles in different immune cells (Table 1). Therefore, it exhibits
pleiotropic properties by participating and integrating with other
signaling pathways, i.e., the Wnt-bcatenin network and sex
hormones receptors (101). The preliminary development of
AhR
-/-
mice showed that AhR deficiency considerably reduced
the lifespan, as indicated by frequent death after birth. Moreover,
in the first few weeks of birth, AhR
-/-
mice also represented a
compromised growth rate (102,103). In addition, AhR
-/-
mice
developed various hepatic abnormalities, such as abnormal
retinoic acid metabolism, transient hepatic steatosis, and bile
duct fibrosis (102–104). Similarly, an in-vivo model of
imiquimod-induced psoriasisexhibitsthat,insteadof
hematopoietic cells, AHR in keratinocytes limits inflammation
(105). Besides, an indole derivative IAId of microbiota-derived
tryptophan metabolite exerts inverse effects on skin
inflammation in atopic dermatitis patients by targeting AhR
(106). It is known that AhR-deficient animals display high
resistance to TCDD, which is an environmental pollutant.
However, an in-depth examination of the immune responses
was lacking (107). AhR regulates allergic diseases in both
canonical and non-canonical pathways. It has been found that
Di(2-ethylhexyl) phthalate (DEHP), a plasticizer, boosts the
ovalbumin-induced allergic rhinitis by activating the AhR
canonical pathway (108). However, a detailed understanding
of the impact of the AhR-canonical signaling pathway on the
AhR-non-canonical signaling pathway hasn’t been studied.
FIGURE 2
Molecular mechanism of an allergens-induced immune response. The host is exposed to multiple sources of allergens daily. Allergens-induced
immune response begins when an allergen is presented to naïve T cells via antigen-presenting cells. Upon activation in the presence of first
allergen exposure, naïve T cell is differentiated into Th2 cells, and the production of IgE by B cells. The IL-10 from APC favors the selective
clonal expansion of Th2 cells, particularly the Th2 memory cells. in case of allergen re-exposure, crosslinking of antibody-loaded high-affinity
IgE receptors is triggered on the surface of mast cells to provoke an acute-phase immune response. Subsequently, several pro-inflammatory
mediators are secreted byTh2 cells, eosinophils, and mast cellsin a late-phase reaction. Besides, Tregs suppressTh2-cell responses by secreting IL-10
and TGF-b. Meanwhile, Th1 secretes various cytokines to achieve cell-mediated immune responses, while Th17 recruits neutrophils and triggers
epithelial cells and fibroblasts to secrete cytokines. IFNg-interferon-g, FceRI, the high-affinity receptor for IgE; TGF-b-transforming growth factor-beta;
APC-antigen presenting cell; IL-interleukin. The illustration is drawn by BioRender (biorender.com).
Riaz et al. 10.3389/fimmu.2022.1057555
Frontiers in Immunology frontiersin.org05

Emerging investigations have specified the profound
influence of AhR signaling on host-pathogen and host-
commensal interactions and in shaping the immune responses
from various cell types. AhR is a critical player in mucosal
interfaces where an individual interacts with environmental
pollutants and other living entities (109,110). As stated, the
AhR might serve a considerably efficient role in mediating
allergic immune responses by acting as an essential factor in
regulating the functions of various immune system cells,
together with B, T, and dendritic cells (18,23,111,112).
Briefly, AhR mediates mast cell differentiation and growth (90,
113), dendritic cell function (114), differentiation of type 1
regulatory T cell (Tr1) (115) and Th9 (116), intraepithelial
lymphocytes functions (117), Treg intestinal homing (118) and
impacts on gd+ T cells homeostasis (119), affects the balance of
Tregs and Th17 cells (120,121), and lymphoid follicles (122). A
brief overview of the role of AhR in immune cells has been
shown in Figure 3. These findings suggest that AhR is critical for
the progression of allergic inflammatory diseases and the
development of allergic and inflammatory responses. However,
the detailed mechanism of the impact of AhR in allergen-
induced allergic inflammation and underlying mechanisms
persist indefinably.
AhR in mast cells to regulate
allergic diseases
As discussed earlier, mast cells are critical to exert adjuvant
functions during exposure to allergens and immune sensitization
in response to these allergens (123,124). Generally, mast cell
produces a broad variety of inflammatory factors to respond to
environmental allergens and initiate immune responses (125).
Activation of rat RBL2H3 mast cell line with AhR endogenous
ligands, kynurenine and kynurenic acid, elevates the level of IL-
6, a well-known AhR downstream target, in a calcium-
dependent manner (126). Later, the expression of AhR was
reported in the rat RBL2H3 mast cell line (127) and the mouse
and human mast cells (90,91). Afterward, several lines of
evidence indicate the role of AhR in the immune regulation of
mast cells. Ligation of AhR with its ligand 6-formylindolo-[3,2-
b]-carbazole (FICZ) potentiate the classical IgE/Ag-dependent
response by elevating the secretion of pro-inflammatory
cytokines IL-6 and IL-13, LTC4 and histamine, through the
activation of PKCdand ERK (90,91). On the other hand, AhR
activation also induces the production of reactive oxygen species
(ROS) in response to AhR activation through mast cells to
impact mast cell-dependent inflammatory responses (128). In
association with this, chronic rhinosinusitis with nasal polyps
(CRSwNP) was found to be associated with mast cell-dependent
oxidant stress and inflammation. Mast cell-specific absence of
AhR, predominantly found in the mast cells of nasal polyps,
reduced ROS production and the expression of oxidized
calmodulin-dependent protein kinase II (ox-CaMKII). This
suggests the role of AhR in regulating the activation of mast
cell by altering the levels of ox-CaMKII and ROS in CRSwNP
patients (129). Meanwhile, genetic ablation of AhR in mast cells
impairs the production of IL-13 and elevates mitochondrial
damage; thus, it participates in the homeostasis and maturation
of mast cells (90).
Interestingly, the response of mast cells is highly dependent
on the duration of FICZ exposure. It was noted that a single dose
of FICZ improved the activation characteristics of mast cells in
terms of secretion of pro-inflammatory IL-6 and histamine. In
contrast, extended exposure to FICZ boosted IL-17 production
and decreased degranulation (91). These IL17+ mast cells were
TABLE 1 Role of potential allergens and AhR ligands on the immune responses in allergic diseases.
Potential allergens/AhR ligands Model Response References
TCDD Non-eosinophilic asthma model Increased Th17 and decreased Treg differentiation (89)
FICZ Mouse bone marrow-derived mast
cells from AhR
-/-
mice
Maturation and activation of mast cells, and secretion of
IL-6 and IL-17 by mast cells
(90,91)
Indoxyl 3-sulfate (I3S) Ovalbumin-sensitized allergic asthma Regulate Th2 differentiation (92)
Ovalbumin aerosol Ovalbumin allergy model T cell activation by dendritic cells (93)
4-nonylphenol Indeno[1,2,3-cd]pyrene Ovalbumin-induced allergic asthma Increased secretion of Th2 cytokines (94,95)
Cockroach extract (CRE B46) Allergic asthma Polarization of M1/M2 macrophages (96)
Urban dust particle (SRM1649b) Enhance Th17 polarization (97)
PM2.5 Cockroach-sensitized mouse model Increased Th17 and decreased Treg differentiation (98)
Non-dioxin-like AhR ligands
(FICZ, b-NF and 6-MCDF)
Peanut allergy model No effect on Treg (99)
Indole-3-carbinol Peanut allergy model Increase in CD11c+ and CD103+MHC-II+ cells (100)
Riaz et al. 10.3389/fimmu.2022.1057555
Frontiers in Immunology frontiersin.org06

also found in the lung parenchyma of patients with chronic
obstructive pulmonary disease (COPD) (91). ORM1 (yeast)-like
protein 3 (ORMDL3), localized in the endoplasmic reticulum
(ER), is pivotal in allergic asthma (130). A recent study illustrates
that AhR ligand, PAH, activates sphingosine-1-phosphate S1P
production, and decreases the activity of S1P lyase (S1PL) in
resting immune cells, IgE/antigen-activated mast cells. This
decreased activity of S1PL is reversed by silencing ORMDL3
or adding an antioxidant, thereby suggesting that the AhR-
ligand axis regulates the time-dependent upregulation of
ORMDL3/S1PL complex, particularly in allergic diseases (131).
Meanwhile, cow/goat milk containing a protein family of
lipocalins or secretoglobins acts as potential respiratory
allergens (132). In another research, beta-lactoglobulin (BLG),
a bovine lipocalin in milk, acts as an allergen and primes human
mast cells for degranulation by facilitating the quercetin-
dependent AhR activation and influencing the expression of
AhR-downstream Cyp1A1 in the lung (133). Conclusively,
increasing data reveal the fundamental involvement of mast
cells in normal and allergic disease conditions. Mast cells affect
the host in allergic diseases and participate in the deregulatory
immune response.
AhR in dendritic cells to regulate
allergic diseases
In response to allergens, DCs are crucial in inducing allergic
sensitization or tolerance (134). As DCs are present and
dispersed across the body, their localization is firmly expressed
by their functions as APCs. Immature DCs exist in the place
where the entry of the first antigen is projected, such as the
urogenital system, upper and lower airways, and the epithelium
of skin and gut mucosa. In the same way as other antigens,
allergens cross cellular barriers to interact with DCs (134). These
cells move to lymphoid organs and transmit antigens to
immature T cells. Either the stimulation of Foxp3+ regulatory
T (Treg) cells or the induction of T helper 2 (Th2) cells would
cause allergic sensitization (135).
FIGURE 3
AhR-dependent regulation of immune cells. Activation of AhR in response to exogenous ligands or allergens influences the activity of adaptive
and innate immune responses. Briefly, AhR affects the polarization of macrophages, the function of Th2 cells, T and B cell differentiation, and
DC functions. These effects of AhR ultimately imbalance the M1/M2 polarization and Th17/Treg balance. The illustration is drawn by BioRender
(biorender.com).
Riaz et al. 10.3389/fimmu.2022.1057555
Frontiers in Immunology frontiersin.org07

Skin-resident specialized DCs can swiftly detect and sample
antigens to determine whether they constitute a health risk.
Langerhans cells (LCs) are dendritic cells found in the skin.
Epidermal LCs were identified as DCs when C3, Fc, and MHC
Class II receptors were found on them, and they have been the
subject of in-depth research ever since (136,137). In the
mammalian dermis, however, new DC subpopulations have
also been found (138).
The level of many co-stimulatory molecules, including
CD54, CD80, and CD86, indicates that epidermal LCs interact
with allergens as soon as they penetrate the skin barrier and get
activated. The secretion of pro-inflammatory cytokines, such as
IL-1, IL-12, and TNF-ais also stimulated concurrently (139).
According to animal studies, this inflammatory process is
followed by the infiltration and buildup of moDC in tissues.
The murine DC markers (CD11c, CD80, CD86, MHC II, and
DEC205) as well as the macrophage-associated markers (Mac-3,
F4/80), and monocyte (CD11b, Ly6C) are expressed by these
cells (140).
CD1a+CD11b+CD1c+ plasmacytoid and myeloid DCs have
been seen in the skin of people with atopic dermatitis (141).
FcR1, a highly affinitive IgE receptor, is expressed by both groups
(142–144). Because oral sensitivity to peanuts is associated with
an elevated inflammatory CD11b+ DCs and a reduction in gut
resident CD103+ DCs, it is crucial for patients with food allergy
to maintain a balance between tolerogenic CD103+ DCs and
inflammatory CD11b+ DCs (145). Mucosal CD103+ DCs have
also been found to stimulate Foxp3+ regulatory T (Treg) cells
through TGF-b1 and retinoic acid, which makes them crucial in
the development of oral tolerance (146–148). Tregs control the
strength of immunological responses and are crucial in
controlling allergic sensitization (149).
Lung APCs, which get exposure to exogenous and
endogenous AhR ligands during the asymptomatic
sensitization phase of the asthmatic response, take up and
process the allergen. The subsequent synthesis of Th2
cytokines and activation of B cells that develop into allergen-
specific IgE-production is triggered by DCs-presentation of
allergen to naïve T cells. These IgE antibodies attach to
basophils and mast cells that express high IgE affinity
receptors in anticipation of future allergen exposure. Both
macrophages and DCs exhibit AhR expression, and new
research indicate that AhR functions upstream of DC by
steering the destiny of human monocytes toward DC rather
than macrophages. This suggests that AhR activation may favor
DC-dependent processes (150). Interestingly, mesenteric lymph
node (MLN) CD103
+
DCs elevate AhRR upon TCDD-
dependent in vivo activation of AhR (151). However, limited
information related to the AhR gene is available in association
with DCs subsets (152).
AhR is extensively expressed in cDCs (101) and is crucial to
control these cells. Multiple tolerogenic processes are activated
in DCs by genomic and non-genomic AhR signaling, which
modifies the production of cytokines essential for effector and
Treg development (153). It has also been demonstrated that AhR
signaling in DCs regulates the expression of metabolites with
significant immunoregulatory roles. For instance, IDO, an
enzyme that catalyzes the formation of the Trp-derived
metabolite kynurenine, is driven by AhR and IL-6, IFN-g,
TNF-a,andIL-1b(154). It’s interesting to note that
kynurenine is an AHR AhR agonist, promoting FoxP3+ Treg
differentiation and reducing inflammation in various situations
(114,155). Interestingly, plant-derived indole-3-carbinol
enhances CD11c+ and CD103+MHC-II+ cells in the lamina
propria of mice induced with peanut allergy (100).
In vitro maturation of AhR-deficient LCs did not raise the
expression of co-stimulatory markers CD40, CD80, and CD24a,
and had a greater phagocytic capability. It’s interesting to note
that AhR-deficient LC had much lower levels of tolerogenic Ido
mRNA expression, and bone marrow-derived dendritic cells
could not be activated by AhR (156). The generation of
tolerogenic splenic CD103+ DCs and the ultimate activation of
Treg cells are linked to in vivo AhR upregulation. Increase in
Treg and the inhibition of the inflammatory response are
thought to be caused by an upsurge in retinoic acid synthesis
by DCs and/or an elevation in the IDO caused by AhR activation
(153,155,157). Altogether, these studies demonstrate how AhR
signaling may activate transcriptional pathways relevant to DC,
making it an attractive option for medical approaches.
AhR in macrophages to regulate
allergic diseases
Macrophages are crucial in establishing adaptive immunity.
These cells respond to various environmental signals and aid the
development of various allergic, autoimmune, infectious, and
non-infectious inflammatory diseases (158). Upon exposure to
allergens, macrophages attain two primary phenotypes: the
classical inflammatory M1 phenotype and the alternative anti-
inflammatory M2 phenotype (159). M1 phenotype is typically
activated by IFN-gand lipopolysaccharide (LPS), which
ultimately elevate the expression of inflammatory genes helpful
for the clearance of intracellular pathogens. Alternatively, the
M2 phenotype is activated by IL-4 and IL-13, which enhance the
expression of anti-inflammatory genes involved in wound
healing (160). Elevated polarization of M2 macrophage was
determined in various allergic diseases, including skin allergies
and allergic asthma (161–163).
Activation of M1 macrophages through LPS elevates the
expression of AhR in macrophages through the NF-kB pathway
(164). The loss of AhR in macrophages diminishes the IL-10
secretion in LPS-activated macrophages. Mechanistically, AhR
was found to be an essential component for the secretion of IL-
10 and the phosphorylation of STAT3 through Src during
Riaz et al. 10.3389/fimmu.2022.1057555
Frontiers in Immunology frontiersin.org08

inflammatory macrophage-dependent immune regulation (164).
Besides, both exogenous (BaP) and endogenous (FICZ) AhR
ligands can enhance the Rac1 ubiquitination, which takes part in
the activation of macrophages through PI3K/AKT-pathway,
ensuing in a pro-inflammatory macrophage phenotype (165).
Meanwhile, AhR has been known to impact the M1/M2
macrophage polarization by influencing arginine and nitric
oxide production. It was determined that macrophage-specific
depletion of AhR accelerates the secretion of pro-inflammatory
cytokines upon stimulation with LPS, affecting the balance
between M1 and M2 macrophages (166). Similarly, ablation of
AhR in tumor-associated macrophages led macrophages
towards a pro-inflammatory phenotype which ultimately
raised the population of intra-tumoral IFNgsecreting CD8
+
T
cells (167). Another study illustrated that AhR exerts a negative
role in the differentiation of monocytes and bone marrow-
derived macrophages (150,168). It was established that the
activation of AhR downregulates the differentiation of
macrophages by influencing the AhR-miR-142a-IRF1/HIF-1a
axis to mitigate M1 macrophage polarization and expand M2
macrophage polarization (169).
In systemic lupus erythematosus, the expression of AhR
is increased on the surface of macrophages susceptible to
apoptotic cells, which eventually promotes the secretion
of immunosuppressive cytokine IL-10; thus, limits the
pathogenesis of SLE in-vivo (170). Meanwhile, in the
cockroach extract (CRE)-induced asthma mouse model, it was
estimated that macrophages polarized from mesenchymal stem
cells shift pro-inflammatory M1 toward an anti-inflammatory
M2 macrophage which was highly dependent on the AhR
signaling. However, the AhR antagonist (CH223191) decreased
the M2 polarization and boosted M1 polarization in mice
challenged with cockroach allergens (96). Overall, it can be
recommended that AhR is decisive in the polarization of M1
and M2 macrophages.
AhR in B cells to regulate
allergic diseases
Antigen-specific B-cell clones are activated and
differentiated in response to the particular antigen when
interacting with a mature naive B cell or with T cells. This
happens in phases, with each stage corresponding to a
modification in the genome level at the antibody loci,
eventually leading to the development of memory B cells,
effector cells (plasma cells), and antibody production (humoral
immunity) (171). The AhR level in the various cells entangled in
the pathogenesis of allergy disorders has been previously
demonstrated. The IL-4 and IL-13 secretion stimulates B cells
to transform them into plasma cells, producing allergen-specific
IgE that binds to high-affinity IgE receptors on the mast cells.
The allergen representation does the Th2 activation to naïve T
cells through APCs (19). For sensitization and the emergence of
the instant bronchospastic response by IgE production, the
humoral response’s development in asthma is crucial.
B cells express AhR, and a prior investigation found that
the AhR agonist [4-(3-chloro-phenyl)-pyrimidin-2-yl]-[4-
trifluoromethyl-phenyl]-amine (VAF347)] suppresses the
production of IgE by B cells (172). The AhR functions in B
cells have recently been reexamined. It has been discovered to
control the destiny decisions of B cells by favoring memory B
cells which suppress the terminally developed antibody-
secreting plasma cells (173). Additionally, the activation of the
Ahr is activated by microbiota-derived butyrate, which helps in
the accumulation of Il-10-secreting regulatory B cells (Bregs)
(174,175).
By inhibiting IgG and IgM production and reducing B cell
development into Ig-secreting cells, TCDD inhibits humoral
immune responses (176). The direct impacts of TCDD on the
growth of B cells have recently been evaluated by Sulentic et al.
(177). In a nutshell, TCDD interferes with B cell-dependent
antibody production and their proliferation at various phases of
B cell maturation and differentiation. B cells are particularly
vulnerable to AhR-ligand TCDD, particularly during their
activation phase, which will ultimately be low vulnerable as
cells move closer to terminal differentiation. B cell activation
produces a significant level of AhR.
Additionally, it’slikelythatTCDDinfluences the
transcription of various genes in B cells AhR-dependent
manner and causes various biochemical modifications which
can be unrelated to AhR-mediated gene transcription (177).
Aside from these direct impacts on B cells, AhR stimulation can
adversely impact the function and the activation activity of B
cells on the Th cells and Th-secreted cytokines. As a result, we
urge that AhR is highly engaged in controlling B cells, and
targeting AhR can promote memory responses.
AhR regulating T cells in
allergic diseases
Airway hyperresponsiveness, eosinophil recruitment, mucus
hypersecretion, and the secretion of the abovementioned
mediators contribute to the initiation and progression of the
allergen-specificinflammatory reaction (178,179). The unique
asthmatic reaction player from the innate lymphoid cell family
(ILC) has more recently been identified as critical for allergic
reactions (180). ILCs are mostly found in mucosal regions, lack
antigen receptor expression, and react to cytokines in their
surroundings. Innate equivalents of Th1, Th2, and Th17/Th22
cells are type 1, 2 and 3 ILCs, respectively, and their cytokine
pattern is similar to that of conventional T helper cell
populations. ILC2 participates in both experimental and
Riaz et al. 10.3389/fimmu.2022.1057555
Frontiers in Immunology frontiersin.org09

clinical allergies by generating airway hyperresponsiveness,
mucus hyperproduction and lung eosinophilia (180). ILC2 also
generates IL-5 and -13 after stimulation by TSLP, IL-25, or -33.
Lung ILC3 has only previously been discovered in a few
experimental asthma types, particularly those that are linked
to obesity (181,182). When AhR activity is increased, the ILC2
function is suppressed, whereas ILC3 function is promoted (111,
183,184). This suggests that AhR favors the generation of Th17-
type cytokines by subtly counter-regulating ILC subsets, with the
best in the gut. Besides the fact that AhR is abundantly found in
ILC2 and ILC3 of the gut, no research has yet looked at how AhR
ligands with allergens cause Th17-type responses, even though
several studies have demonstrated this.
While the induction of Treg is considered advantageous,
some kinds of asthma have a high Th17 profile that may be a
factor in their severity. Th17 cells are a well-known immune
regulator subgroup of CD4+ T cells that secrete the cytokines
interleukin (IL)-17 (also known as IL-17A), IL-17F, and IL-22.
AhR activation promotes T helper (Th)17 cell development,
which worsens in vivo Th17 cell-mediated autoimmunity (such
as EAE) (120). In a model of the ovalbumin-induced allergic
disease model, it was studied that AhR regulates the
differentiation of T cells by dendritic cells (93). The levels of
AhR expression vary among the T cell subsets, with Th17 and
Treg cells expressing the most AhR and Th1 and Th2 cells the
least (185). It was undermined that indoxyl 3-sulfate (I3S) acts as
AhR ligand and regulates the differentiation of Th2 cells in the
ovalbumin-sensitized allergic asthma model (92). The AhR also
modulates the production of cytokines by Th2 cells. 4-
nonylphenol Indeno[1,2,3-cd]pyrene is a prominent air
pollutant that increases the secretion of cytokines from Th2
cells in an ovalbumin-induced allergic asthma model (94,95).
AhR became a major player in the control of T cell biology in the
2000s. It has been demonstrated that AhR is increased during
the maturation of Th17 cells, which increases the synthesis of IL-
17 and IL-22 in mice (120,121,186) and IL-22 in humans (187,
188). As a result, Th17 cell production of IL-22 is reduced in
AhR-deficient animals (120). However, AhR ligands may exert
different effects on the Th17-mediated allergic response
outcomes through FICZ as favoring and TCDD as inhibiting
this profile (120,121). During Th17 development, signal
transducer and transcription 3 are activated, which causes
AhR expression to increase (115). AhR also inhibits Stat5 and
Stat1 signaling, which would otherwise prevent Th17 formation
and create a positive feedback loop (186). It was also found that
urban dust particle (SRM1649b) enhances Th17 polarization
(97). Thus, AhR could contribute to the early phases of Th17
differentiation, but additional elements are necessary for the
growth of fully pathogenic effector Th17 cells (189).
AhR activation has also been connected to type 1 T
regulatory cells (Tr1) cells (secreting IL-10) and Foxp3
expressing Tregs (190,191). AhR ligands like TCDD or
kynurenine boost Foxp3 expression by a variety of methods,
including epigenetic changes in T cells and regulation of DC, in
contrast to FICZ, which encourages differentiation of Th17 cells
in both non-eosinophilic asthma model and cockroach-
sensitized mouse model (89,98,99,155,192). These
epigenetic T cell changes, particularly DNA methylation,
promote plasticity and flexibility among CD4+ T cells and
enable differentiation of various subpopulations (193).
Increased FOXP3 methylations in peripheral Treg cells in
asthma patients have been more linked to their impaired
functions in a high ambient air pollution environment than
asthmatics in an environment with low air pollution (194). It is
noteworthy that, other than TCDD, the non-dioxin-like AhR
ligands, such as FICZ, b-NF, and 6-MCDF, exert no significant
effect on the Treg in the peanut-induced allergy model (99).
Alternatively, Il-27, known as a cytokine with pleiotropic
activity while performing various immune regulatory actions,
has been shown to increase Tr1 cells’AhR expression through a
process mediated by Stat3 (195). The immunosuppressive
cytokine IL-10 is secreted by Tr1 cells because of this
activation-dependent effect on their transcriptional program. It
is notable that activin-A, one of the members of the TGF-family,
can stimulate the level of AhR and IRF4 transcription factors in
human CD4+ T cells, resulting in the development of Tr1-like
cells capable of suppressing the reactions to allergens in a mouse
model (196). It is interesting to note that AhR can change
mature Th17 cells into Tr1 cells that produce IL-10 (197), a
mechanism evident in allergic rhinitis (198). Therefore, it is
worth associating the AhR with the plasticity of Th17 cells that
need stimulus to differentiate into regulatory Tr1 cells or
pathogenic Th17 cells.
AhR ligands encourage the production of Foxp3 Tr1-like
cells on human CD4+ T cells, which inhibit through granzyme B
and produce IL-10. Additionally, AhR ligands, in the presence of
TGF-b1, activate the Foxp3+ Treg, which suppresses by
activating CD39, an enzyme that hydrolyzes ATP to AMP.
SMAD1 is induced by TGF-b1andAhRligandsina
mechanism that encourages Foxp3 expression by binding to
the Foxp3 enhancer. Aiolos, which binds to Foxp3 and inhibits
IL-2 production, is also produced to counter the AhR ligands
and TGF-b1(191,199). AhR is also implicated in the trans-
differentiation of Th17 to Tr1 since AhR agonists facilitate this
process (197). AhR modulates Tr1 cell metabolism in the late
phases when Hif-1 is no longer expressed (115). Interestingly,
AhR and TGF-b1 form a functional axis that advances the
allergic airway inflammation induced by cockroach
allergens (200).
Of note, AhR is indispensable for developing Th17 and Tr1
cells along with the IL-6-dependent Th22 cells, which secrete IL-
22 and function as a defense against enteropathogenic bacteria
(201,202). Meanwhile, besides the role of AhR in the
differentiation of CD4+ cells, it has been evident that AhR also
alters the CD8+ T cell responses in an antigen-specific manner.
AhR deficiency disrupts the primary CD8+ cell responses in
Riaz et al. 10.3389/fimmu.2022.1057555
Frontiers in Immunology frontiersin.org10

response to influenza virus-related infections in a cell-extrinsic
way (203). Meanwhile, it has been noted that during the
silencing of AhR, CD8+ T cells with antigen-specificity can
display altered patterns of DNA methylation and an aberrant
transcriptional profile suggesting the presence of exhausted CD8
T cells (204). The retention and/or survival of tissue-resident
memory CD8 T lymphocytes in the skin is also regulated by
AhR (205).
The role of AhR in gdT cell biology has also been well
established. It was illustrated that IL-17-secreting innate-like gd
T cells (206,207) increase the level of AhR, which ultimately play
a pivotal role in the production of IL-22 by gd T cells (208).
Similarly, AhR signaling also plays a crucial role in maintaining
the population of skin-resident Vg3+ gd T cells, also recognized
as Dendritic Epidermal gd T cells (DECT), which originate from
thymic precursors and move to the skin during early stages of
life (117,119). Moreover, for the survival and maintenance of
both CD8aa+ TCRab+ cells and Vg5+ gd T cells, intraepithelial
lymphocytes in small intestinal LP, the presence of AhR ligands
in the food is an essential factor (117). Together, these
investigations support the notion that AhR in T cell subsets
continuously interacts with the environmental cues at the
mucosal level and responds to the microbial products.
Conclusion
In conclusion, AhR controls the innate and adaptive response
at a variety of levels, with consequences that are expected to vary
depending on ancestry and the results of the asthmatic reaction.
These results demonstrate positive and negative impacts on the
allergens-specific response when using gene silencing, knockout
mice, or AhR antagonists. Even though AhR was cloned more
than 20 years ago, there is still much we don’t know about how it
works in health and diseases. Recent research amply supports the
notion that AhR plays a critical function in immune responses far
beyond the mere identification of contaminants. However, the
AhR crystal structure is still a mystery, and nothing is known
about how nutritional, environmental, bacterial, and endogenous
ligands interact with one another to influence AhR signaling.
The molecular dissection for the deep understanding of AhR
signaling has focused mainly on AhR-canonical signaling, which
generally represents the association of exposure to environmental
pollutants with the diverse pathophysiological effects in an AhR-
dependent manner. This canonical signaling is associated with the
AhR heterodimerization with ARNT and XREs. It has been
demonstrated that the Th1/Th2 cell balance, regulatory T cells,
and dendritic cells are among the immune system cells that are
impacted by the activation of the AhR in response to dioxins. Due
to their involvement in the development of either tolerance or
allergic sensitization, these cells, as previously mentioned, play a
significant part in numerous allergies. Activating the AhR by
dioxin-like substances has recently been demonstrated to decrease
allergy sensitization by reducing the absolute number of precursor
and effector T cells, maintaining CD4+CD25+Foxp3+ Treg cells,
and altering DCs and their interaction with effector T cells in
peanut allergy model (18,209). However, in several diseases, AhR
interacts with and influences numerous other genes, including
Eraand NF-kB, in a non-canonical pathway. Our unpublished
data shows CCl
4
, which is not a ligand for AhR and induces
hepatic inflammation, also influences the accumulation of
immune cells in the inflamed liver and decreases the hepatic
disease severity after the knockout AhR in Tregs. Additionally, a
previous study also suggests that binding of AhR with Eraexhibits
higher affinity compared to ARNT, and alterations of AhR
signaling significantly influence the functions of Tregs in
autoimmune hepatitis (210). Thus, blocking the AhRR and Era
can potentially reestablish immune homeostasis in autoimmune
diseases and other immune-mediated diseases.
Several lines of research suggest that the AhR pathway may
be a valuable target for diseases, e.g., multiple sclerosis,
inflammatory bowel disorders, psoriasis, cancer, and stem cell
transplantation, although caution is still advised. Most likely, to
get the intended outcomes, AhR activation has to be strictly
regulated. For instance, proper wound healing and defense
against bacterial infections are controlled by AhR-dependent
IL-22 secretion from innate and adaptive cells. However, IL-22
production that is persistent and dysregulated develops into a
pathogen and causes colitis and cancer (211,212).
We have discussed that AhR is pivotal in modulating the
effects on the immune response. As AhR interacts with various
exogenous ligands, it serves as a potential target for numerous
small molecules for the therapeutic intervention. It was reported
that tapinarof and laquinimod could significantly target the AhR
to treat multiple sclerosis, atopic dermatitis, and psoriasis (213–
215). Similarly, metformin, which acts as an anti-diabetic drug,
can also influence the activity of AhR in mast cells to treat
allergic diseases (216). Similar tight regulation is probably
crucial in many biological processes that AhR regulates.
However, the presence of AhR in numerous tissues and cell
types is challenging to treat AhR signaling pathway. Therefore,
cell-specific delivery should also be considered to target this
pathway. For instance, targeted delivery of chemically modified
Foxp3 mRNA to sites of inflammation in the house dust mite-
induced allergic asthma served as a safe and efficient therapeutic
tool by regulating T cell immune responses (217). Overall, it
appears that AhR pathway is activated through numerous
signals from several sources to ensure that the host responds
accurately and adapts to ongoing environmental changes and
allergens, a step crucial to adaptation.
Author contributions
FR, FP, WP outlined the manuscript,FR drafted it. FP and
PW reviewed and improved the rigorousness of the manuscript.
Riaz et al. 10.3389/fimmu.2022.1057555
Frontiers in Immunology frontiersin.org11

FP and PW supervised the study. All authors contributed to the
article and approved the submitted version.
Funding
FP is supported by the National Key R&D Program of China
(2021YFC2400500), the Shenzhen Science and Technology
Program (KQTD20210811090115019), the National Natural
Science Foundation of China (Grant 32170925), and the start-
up fund of SIAT, CAS. PW is supported by Natural Science
Foundation of Chongqing Grant CSTB2022NSCQ-MSX1069,
Entrepreneurship and Innovation Support Program of
Chongqing for overseas Scholars Grant CX2022118.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could
be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the
authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed
or endorsed by the publisher.
References
1. Gu YZ, Hogenesch JB, Bradfield CA. The PAS superfamily: sensors of
environmental and developmental signals. Annu Rev Pharmacol Toxicol (2000)
40:519–61. doi: 10.1146/annurev.pharmtox.40.1.519
2. Frericks M, Meissner M, Esser C. Microarray analysis of the AHR system:
tissue-specificflexibility in signal and target genes. Toxicol Appl Pharmacol (2007)
220(3):320–32. doi: 10.1016/j.taap.2007.01.014
3. Kewley RJ, Whitelaw ML, Chapman-Smith A. The mammalian basic helix-
loop-helix/PAS family of transcriptional regulators. Int J Biochem Cell Biol (2004)
36(2):189–204. doi: 10.1016/S1357-2725(03)00211-5
4. Denison MS, Nagy SR. Activation of the aryl hydrocarbon receptor by
structurally diverse exogenous and endogenous chemicals. Annu Rev Pharmacol
Toxicol (2003) 43:309–34. doi: 10.1146/annurev.pharmtox.43.100901.135828
5. Manners S, Alam R, Schwartz DA, Gorska MM. A mouse model links asthma
susceptibility to prenatal exposure to diesel exhaust. J Allergy Clin Immunol (2014)
134(1):63–72. doi: 10.1016/j.jaci.2013.10.047
6. Stevens EA, Mezrich JD, Bradfield CA. The aryl hydrocarbon receptor: a
perspective on potential roles in the immune system. Immunology (2009) 127
(3):299–311. doi: 10.1111/j.1365-2567.2009.03054.x
7. Gutierrez-Vazquez C, Quintana FJ. Regulation of the immune response by
the aryl hydrocarbon receptor. Immunity (2018) 48(1):19–33. doi: 10.1016/
j.immuni.2017.12.012
8. Nguyen LP, Bradfield CA. The search for endogenous activators of the aryl
hydrocarbon receptor. Chem Res Toxicol (2008) 21(1):102–16. doi: 10.1021/tx7001965
9. Rothhammer V, Quintana FJ. The aryl hydrocarbon receptor: an
environmental sensor integrating immune responses in health and disease. Nat
Rev Immunol (2019) 19(3):184–97. doi: 10.1038/s41577-019-0125-8
10. Quintana FJ, Sherr DH. Aryl hydrocarbon receptor control of adaptive
immunity. Pharmacol Rev (2013) 65(4):1148–61. doi: 10.1124/pr.113.007823
11. Torti MF, Giovannoni F, Quintana FJ, Garcı

a CC. The aryl hydrocarbon
receptor as a modulator of anti-viral immunity. Front Immunol (2021) 12:624293.
doi: 10.3389/fimmu.2021.624293
12. Lawrence BP, Vorderstrasse BA. New insights into the aryl hydrocarbon
receptor as a modulator of host responses to infection. Semin Immunopathol (2013)
35(6):615–26. doi: 10.1007/s00281-013-0395-3
13. Girer NG, Tomlinson CR, Elferink CJ. The aryl hydrocarbon receptor in
energy balance: The road from dioxin-induced wasting syndrome to combating
obesity with ahr ligands. Int J Mol Sci (2020) 22(1):49. doi: 10.3390/ijms22010049
14. Lin YH, Luck H, Khan S, Schneeberger PHH, Tsai S, Clemente-Casares X,
et al. Aryl hydrocarbon receptor agonist indigo protects against obesity-related
insulin resistance through modulation of intestinal and metabolic tissue immunity.
Int J Obes (Lond) (2019) 43(12):2407–21. doi: 10.1038/s41366-019-0340-1
15. Wang B, Zhou Z, Li L. Gut microbiota regulation of AHR signaling in liver
disease. Biomolecules (2022) 12(9):1244. doi: 10.3390/biom12091244
16. Perepechaeva ML, Grishanova AY. The role of aryl hydrocarbon receptor
(AhR) in brain tumors. Int J Mol Sci (2020) 21(8):2863. doi: 10.3390/ijms21082863
17. Xue P, Fu J, Zhou Y. The aryl hydrocarbon receptor and tumor immunity.
Front Immunol (2018) 9:286. doi: 10.3389/fimmu.2018.00286
18. Schulz VJ, Smit JJ, Pieters RH. The aryl hydrocarbon receptor and food
allergy. Vet Q (2013) 33(2):94–107. doi: 10.1080/01652176.2013.804229
19. Poulain-Godefroy O, BouteM, Carrard J, Alvarez-Simon D, Tsicopoulos A,
de Nadai P. The aryl hydrocarbon receptor in asthma: Friend or foe? Int J Mol Sci
(2020) 21(22):8797. doi: 10.3390/ijms21228797
20. Yi T, Wang J, Zhu K, Tang Y, Huang S, Shui X, et al. Aryl hydrocarbon
receptor: A new player of pathogenesis and therapy in cardiovascular diseases.
BioMed Res Int 2018 (2018) p:6058784.
21. Harper PA, Riddick DS, Okey AB. Regulating the regulator: factors that
control levels and activity of the aryl hydrocarbon receptor. Biochem Pharmacol
(2006) 72(3):267–79. doi: 10.1016/j.bcp.2006.01.007
22. Yamamoto J, Ihara K, Nakayama H, Hikino S, Satoh K, Kubo N, et al.
Characteristic expression of aryl hydrocarbon receptor repressor gene in human
tissues: organ-specific distribution and variable induction patterns in mononuclear
cells. Life Sci (2004) 74(8):1039–49. doi: 10.1016/j.lfs.2003.07.022
23.ShindeR,McGahaTL.Thearylhydrocarbon receptor: Connecting
immunity to the microenvironment. Trends Immunol (2018) 39(12):1005–20.
doi: 10.1016/j.it.2018.10.010
24. Cella M, Colonna M. Aryl hydrocarbon receptor: Linking environment to
immunity. Semin Immunol (2015) 27(5):310–4. doi: 10.1016/j.smim.2015.10.002
25. Dong B, Cheng W, Li W, Zheng J, Wu D, Matsumura F, et al. FRET analysis
of protein tyrosine kinase c-src activation mediated via aryl hydrocarbon receptor.
Biochim Biophys Acta (2011) 1810(4):427–31. doi: 10.1016/j.bbagen.2010.11.007
26. Dou H, Duan Y, Zhang X, Yu Q, Di Q, Song Y, et al. Aryl hydrocarbon
receptor (AhR) regulates adipocyte differentiation by assembling CRL4B ubiquitin
ligase to target PPARgfor proteasomal degradation. J Biol Chem (2019) 294
(48):18504–15. doi: 10.1074/jbc.RA119.009282
27. Ohtake F, Baba A, Takada I, Okada M, Iwasaki K, Miki H, et al. Dioxin
receptor is a ligand-dependent E3 ubiquitin ligase. Nature (2007) 446(7135):562–6.
doi: 10.1038/nature05683
28. Cox MB, Miller 3CA. The p23 co-chaperone facilitates dioxin receptor
signaling in a yeast model system. Toxicol Lett (2002) 129(1-2):13–21. doi: 10.1016/
S0378-4274(01)00465-9
29. Uemura S, Nakajima Y, Yoshida Y, Furuya M, Matsutani S, Kawate S, et al.
Biochemical properties of human full-length aryl hydrocarbon receptor (AhR).
J Biochem (2020) 168(3):285–94. doi: 10.1093/jb/mvaa047
30. Meyer BK, Perdew GH. Characterization of the AhR-hsp90-XAP2 core
complex and the role of the immunophilin-related protein XAP2 in AhR
stabilization. Biochemistry (1999) 38(28):8907–17. doi: 10.1021/bi982223w
31. Perdew GH. Association of the ah receptor with the 90-kDa heat shock
protein. J Biol Chem (1988) 263(27):13802–5. doi: 10.1016/S0021-9258(18)68314-0
32. Pongratz I, Mason GG, Poellinger L. Dual roles of the 90-kDa heat shock
protein hsp90 in modulating functional activities of the dioxin receptor. evidence
Riaz et al. 10.3389/fimmu.2022.1057555
Frontiers in Immunology frontiersin.org12

that the dioxin receptor functionally belongs to a subclass of nuclear receptors
which require hsp90 both for ligand binding activity and repression of intrinsic
DNA binding activity. J Biol Chem (1992) 267(19):13728–34. doi: 10.1016/S0021-
9258(18)42274-0
33. Carver LA, LaPres JJ, Jain S, Dunham EE, Bradfield CA. Characterization of
the ah receptor-associated protein, ARA9. J Biol Chem (1998) 273(50):33580–7.
doi: 10.1074/jbc.273.50.33580
34. Kazlauskas A, Poellinger L, Pongratz I. The immunophilin-like protein
XAP2 regulates ubiquitination and subcellular localization of the dioxin receptor.
J Biol Chem (2000) 275(52):41317–24. doi: 10.1074/jbc.M007765200
35. Lees MJ, Peet DJ, Whitelaw ML. Defining the role for XAP2 in stabilization of the
dioxin receptor. JBiolChem(2003) 278(38):35878–88. doi: 10.1074/jbc.M302430200
36. Ikuta T, Eguchi H, Tachibana T, Yoneda Y, Kawajiri K. Nuclear localization
and export signals of the human aryl hydrocarbon receptor. J Biol Chem (1998) 273
(5):2895–904. doi: 10.1074/jbc.273.5.2895
37. Ikuta T, Kobayashi Y, Kawajiri K. Phosphorylation of nuclear localization
signal inhibits the ligand-dependent nuclear import of aryl hydrocarbon receptor.
Biochem Biophys Res Commun (2004) 317(2):545–50. doi: 10.1016/j.bbrc.
2004.03.076
38. Tsuji N, Fukuda K, Nagata Y, Okada H, Haga A, Hatakeyama S, et al. The
activation mechanism of the aryl hydrocarbon receptor (AhR) by molecular
chaperone HSP90. FEBS Open Bio (2014) 4:796–803. doi: 10.1016/j.fob.2014.09.003
39. Pappas B, Yang Y, Wang Y, Kim K, Chung HJ, Cheung M. p23 protects the
human aryl hydrocarbon receptor from degradation via a heat shock protein 90-
independent mechanism. Biochem Pharmacol (2018) 152:34–44. doi: 10.1016/
j.bcp.2018.03.015
40. Kazlauskas A, Sundström S, Poellinger L, Pongratz I. The hsp90 chaperone
complex regulates intracellular localization of the dioxin receptor. Mol Cell Biol
(2001) 21(7):2594–607. doi: 10.1128/MCB.21.7.2594-2607.2001
41. Davarinos NA, Pollenz RS. Aryl hydrocarbon receptor imported into the
nucleus following ligand binding is rapidly degraded via the cytosplasmic
proteasome following nuclear export. J Biol Chem (1999) 274(40):28708–15. doi:
10.1074/jbc.274.40.28708
42. Reyes H, Reisz-Porszasz S, Hankinson O. Identification of the ah receptor
nuclear translocator protein (Arnt) as a component of the DNA binding form of
the ah receptor. Science (1992) 256(5060):1193–5. doi: 10.1126/science.
256.5060.1193
43. Seok SH, Lee W, Jiang L, Molugu K, Zheng A, Li Y, et al. Structural
hierarchy controlling dimerization and target DNA recognition in the AHR
transcriptional complex. Proc Natl Acad Sci U.S.A. (2017) 114(21):5431–6. doi:
10.1073/pnas.1617035114
44. Larigot L, Juricek L, Dairou J, Coumoul X. AhR signaling pathways and
regulatory functions. Biochim Open (2018) 7:1–9. doi: 10.1016/j.biopen.
2018.05.001
45. Henry EC, Gasiewicz TA. Transformation of the aryl hydrocarbon receptor
to a DNA-binding form is accompanied by release of the 90 kDa heat-shock
protein and increased affinity for 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochem J
(1993) 294(Pt 1):95–101. doi: 10.1042/bj2940095
46. Wright EJ, De Castro KP, Joshi AD, Elferink CJ. Canonical and non-
canonical aryl hydrocarbon receptor signaling pathways. Curr Opin Toxicol (2017)
2:87–92. doi: 10.1016/j.cotox.2017.01.001
47. Furman DP, Oshchepkova EA, Oshchepkov DY, Shamanina MY,
Mordvinov VA. Promoters of the genes encoding the transcription factors
regulating the cytokine gene expression in macrophages contain putative binding
sites for aryl hydrocarbon receptor. Comput Biol Chem (2009) 33(6):465–8. doi:
10.1016/j.compbiolchem.2009.10.004
48. Durrin LK, Jones PB, Fisher JM, Galeazzi DR, Whitlock JP Jr. 2,3,7,8-
tetrachlorodibenzo-p-dioxin receptors regulate transcription of the cytochrome
P1-450 gene. J Cell Biochem (1987) 35(2):153–60. doi: 10.1002/jcb.240350208
49. Beischlag TV, Wang S, Rose DW, Torchia J, Reisz-Porszasz S, Muhammad
K, et al. Recruitment of the NCoA/SRC-1/p160 family of transcriptional
coactivators by the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear
translocator complex. MolCellBiol(2002) 22(12):4319–33. doi: 10.1128/
MCB.22.12.4319-4333.2002
50. Wang S, Hankinson O. Functional involvement of the Brahma/SWI2-
related gene 1 protein in cytochrome P4501A1 transcription mediated by the
aryl hydrocarbon receptor complex. J Biol Chem (2002) 277(14):11821–7. doi:
10.1074/jbc.M110122200
51. Schnekenburger M, Peng L, Puga A. HDAC1 bound to the Cyp1a1
promoter blocks histone acetylation associated with ah receptor-mediated trans-
activation. Biochim Biophys Acta (2007) 1769(9-10):569–78. doi: 10.1016/
j.bbaexp.2007.07.002
52. Hankinson O. Role of coactivators in transcriptional activation by the aryl
hydrocarbon receptor. Arch Biochem Biophys (2005) 433(2):379–86. doi: 10.1016/
j.abb.2004.09.031
53. Kimura A, Naka T, Nakahama T, Chinen I, Masuda K, Nohara K, et al. Aryl
hydrocarbon receptor in combination with Stat1 regulates LPS-induced
inflammatory responses. JExpMed(2009) 206(9):2027–35. doi: 10.1084/
jem.20090560
54. Yeste A, Takenaka MC, Mascanfroni ID, Nadeau M, Kenison JE, Patel B,
et al. Tolerogenic nanoparticles inhibit T cell-mediated autoimmunity through
SOCS2. Sci Signal (2016) 9(433):ra61. doi: 10.1126/scisignal.aad0612
55. Vogel CF, Matsumura F. A new cross-talk between the aryl hydrocarbon
receptor and RelB, a member of the NF-kappaB family. Biochem Pharmacol (2009)
77(4):734–45. doi: 10.1016/j.bcp.2008.09.036
56. Kim DW, Gazourian L, Quadri SA, Romieu-Mourez R, Sherr DH,
Sonenshein GE, et al. The RelA NF-kappaB subunit and the aryl hydrocarbon
receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells.
Oncogene (2000) 19(48):5498–506. doi: 10.1038/sj.onc.1203945
57. Vogel CF, Sciullo E, Li W, Wong P, Lazennec G, Matsumura F, et al. RelB, a
new partner of aryl hydrocarbon receptor-mediated transcription. Mol Endocrinol
(2007) 21(12):2941–55. doi: 10.1210/me.2007-0211
58. Wilson SR, Joshi AD, Elferink CJ. The tumor suppressor kruppel-like factor
6 is a novel aryl hydrocarbon receptor DNA binding partner. J Pharmacol Exp Ther
(2013) 345(3):419–29. doi: 10.1124/jpet.113.203786
59. Murray IA, Morales JL, Flaveny CA, Dinatale BC, Chiaro C, Gowdahalli K,
et al. Evidence for ligand-mediated selective modulation of aryl hydrocarbon
receptor activity. Mol Pharmacol (2010) 77(2):247–54. doi: 10.1124/mol.
109.061788
60. Warner JO, Kaliner MA, Crisci CD, Del Giacco S, Frew AJ, Liu GH, et al.
Allergy practice worldwide: a report by the world allergy organization specialty and
training council. Int Arch Allergy Immunol (2006) 139(2):166–74. doi: 10.1159/
000090502
61. Kay AB. Allergy and allergic diseases. first of two parts. N Engl J Med (2001)
344(1):30–7. doi: 10.1056/NEJM200101043440106
62. Lee TK, Jeon YJ, Jung SJ. Bi-directional association between allergic rhinitis
and diabetes mellitus from the national representative data of south Korea. Sci Rep
(2021) 11(1):4344. doi: 10.1038/s41598-021-83787-9
63. Hwang CY, Chen YJ, Lin MW, Chen TJ, Chu SY, Chen CC, et al. Cancer risk
in patients with allergic rhinitis, asthma and atopic dermatitis: a nationwide cohort
study in Taiwan. Int J Cancer (2012) 130(5):1160–7. doi: 10.1002/ijc.26105
64. Amritwar AU, Lowry CA, Brenner LA, Hoisington AJ, Hamilton R, Stiller
JW, et al. Mental health in allergic rhinitis: Depression and suicidal behavior. Curr
Treat Options Allergy (2017) 4(1):71–97. doi: 10.1007/s40521-017-0110-z
65. Tseng CH, Chen JH, Lin CL, Kao CH. Risk relation between rhinitis and
acute ischemic stroke. Allergy Asthma Proc (2015) 36(6):e106–12. doi: 10.2500/
aap.2015.36.3891
66. Crans Yoon AM, Chiu V, Rana JS, Sheikh J. Association of allergic rhinitis,
coronary heart disease, cerebrovascular disease, and all-cause mor tality. Ann
Allergy Asthma Immunol (2016) 117(4):359–364.e1. doi: 10.1016/j.anai.
2016.08.021
67. Raj D, Kabra SK, Lodha R. Childhood obesity and risk of allergy or asthma.
Immunol Allergy Clin North Am (2014) 34(4):753–65. doi: 10.1016/j.iac.
2014.07.001
68. Ma J, Xiao L, Knowles SB. Obesity, insulin resistance and the prevalence of
atopy and asthma in US adults. Allergy (2010) 65(11):1455–63. doi: 10.1111/j.1398-
9995.2010.02402.x
69. Thuesen BH, Husemoen LL, Hersoug LG, Pisinger C, Linneberg A. Insulin
resistance as a predictor of incident asthma-like symptoms in adults. Clin Exp
Allergy (2009) 39(5):700–7. doi: 10.1111/j.1365-2222.2008.03197.x
70. Hashimoto Y, Futamura A. Prevalence of allergic rhinitis is lower in subjects
with higher levels of fasting plasma glucose. Diabetes Care (2010) 33(11):e143. doi:
10.2337/dc10-1338
71. Sicherer SH, Sampson HA. Peanut allergy: emerging concepts and
approaches for an apparent epidemic. J Allergy Clin Immunol (2007) 120(3):491–
503. doi: 10.1016/j.jaci.2007.07.015
72. Keet CA, Wood RA, Matsui EC. Limitations of reliance on specific IgE for
epidemiologic surveillance of food allergy. J Allergy Clin Immunol (2012) 130
(5):1207–1209.e10. doi: 10.1016/j.jaci.2012.07.020
73. Steering Committee Authors; Review Panel Members. A WAO - ARIA - GA(2)
LEN consensus document on molecular-based allergy diagnosis (PAMD@): Update
2020. World Allergy Organ J (2020) 13(2):100091 doi: 10.1016/j.waojou.2019.100091
74. Matricardi PM, Kleine-Tebbe J, Hoffmann HJ, Valenta R, Hilger C,
Hofmaier S, et al. EAACI molecular allergology user's guide. Pediatr Allergy
Immunol (2016) 27 Suppl 23:1–250. doi: 10.1111/pai.12563
75. Eder W, Ege MJ, von Mutius E. The asthma epidemic. N Engl J Med (2006)
355(21):2226–35. doi: 10.1056/NEJMra054308
76. Hammad H, Lambrecht BN. Recent progress in the biology of airway
dendritic cells and implications for understanding the regulation of asthmatic
Riaz et al. 10.3389/fimmu.2022.1057555
Frontiers in Immunology frontiersin.org13

inflammation. J Allergy Clin Immunol (2006) 118(2):331–6. doi: 10.1016/
j.jaci.2006.03.041
77. Glimcher LH. Trawling for treasure: tales of T-bet. Nat Immunol (2007) 8
(5):448–50. doi: 10.1038/ni0507-448
78. Broide DH. Molecular and cellular mechanisms of allergic disease. J Allergy
Clin Immunol (2001) 108(2 Suppl):S65–71. doi: 10.1067/mai.2001.116436
79. von Garnier C, Wikstrom ME, Zosky G, Turner DJ, Sly PD, Smith M, et al.
Allergic a irways disease develops after an increase in allerg en capture and
processing in the airway mucosa. J Immunol (2007) 179(9):5748–59. doi:
10.4049/jimmunol.179.9.5748
80. Cousins DJ, Lee TH, Staynov DZ. Cytokine coexpression during human
Th1/Th2 cell differentiation: direct evidence for coordinated expression of Th2
cytokines. J Immunol (2002) 169(5):2498–506. doi: 10.4049/jimmunol.169.5.2498
81. Romagnani S. Regulation of the T cell response. Clin Exp Allergy (2006) 36
(11):1357–66. doi: 10.1111/j.1365-2222.2006.02606.x
82. Bacher P, Heinrich F, Stervbo U, Nienen M, Vahldieck M, Iwert C, et al.
Regulatory T cell specificity directs tolerance versus allergy against aeroantigens in
humans. Cell (2016) 167(4):1067–1078.e16. doi: 10.1016/j.cell.2016.09.050
83. Bacchetta R, Gambineri E, Roncarolo MG. Role of regulatory T cells and
FOXP3 in human diseases. J Allergy Clin Immunol (2007) 120(2):227–35. doi:
10.1016/j.jaci.2007.06.023
84. LarcheM. Regulatory T cells in allergy and asthma. Chest (2007) 132
(3):1007–14. doi: 10.1378/chest.06-2434
85. Schäfer T, Ring J. Epidemiology of allergic diseases. Allergy (1997) 52(38
Suppl):14–22. doi: 10.1111/j.1398-9995.1997.tb04864.x
86. Hartert TV, Peebles Jr. RS. Epidemiology of asthma: the year in review. Curr
Opin Pulm Med (2000) 6(1):4–9. doi: 10.1097/00063198-200001000-00002
87. Matucci A, Vultaggio A, Maggi E, Kasujee I. Is IgE or eosinophils the key
player in allergic asthma pathogenesis? are we asking the right question? Respir Res
(2018) 19(1):113. doi: 10.1186/s12931-018-0813-0
88. Vogel CFA, Van Winkle LS, Esser C, Haarmann-Stemmann T. The aryl
hydrocarbon receptor as a target of environmental stressors - implications for
pollution mediated stress and inflammatory responses. Redox Biol (2020)
34:101530. doi: 10.1016/j.redox.2020.101530
89. Li XM, Peng J, Gu W, Guo XJ. TCDD-induced activation of aryl
hydrocarbon receptor inhibits Th17 polarization and regulates non-eosinophilic
airway inflammation in asthma. PloS One (2016) 11(3):e0150551. doi: 10.1371/
journal.pone.0150551
90. Zhou Y, Tung HY, Tsai YM, Hsu SC, Chang HW, Kawasaki H, et al. Aryl
hydrocarbon receptor controls murine mast cell homeostasis. Blood (2013) 121
(16):3195–204. doi: 10.1182/blood-2012-08-453597
91. Sibilano R, Frossi B, Calvaruso M, Danelli L, Betto E, Dall'Agnese A, et al.
The aryl hydrocarbon receptor modulates acute and late mast cell responses.
J Immunol (2012) 189(1):120–7. doi: 10.4049/jimmunol.1200009
92. Hwang YJ, Yun MO, Jeong KT, Park JH. Uremic toxin indoxyl 3-sulfate
regulates the differentiation of Th2 but not of Th1 cells to lessen allergic asthma.
Toxicol Lett (2014) 225(1):130–8. doi: 10.1016/j.toxlet.2013.11.027
93. Thatcher TH, Williams MA, Pollock SJ, McCarthy CE, Lacy SH, Phipps RP,
et al. Endogenous ligands of the aryl hydrocarbon receptor regulate lung dendritic
cell function. Immunology (2016) 147(1):41–54. doi: 10.1111/imm.12540
94. Wong TH, Lee CL, Su HH, Lee CL, Wu CC, Wang CC, et al. A prominent
air pollutant, Indeno[1,2,3-cd]pyrene, enhances allergic lung inflammation via aryl
hydrocarbon receptor. Sci Rep (2018) 8(1):5198. doi: 10.1038/s41598-018-23542-9
95. Suen JL, Hsu SH, Hung CH, Chao YS, Lee CL, Lin CY, et al. A common
environmental pollutant, 4-nonylphenol, promotes allergic lung inflammation in a
murine model of asthma. Allergy (2013) 68(6):780–7. doi: 10.1111/all.12156
96. Cui Z, Feng Y, Li D, Li T, Gao P, Xu T, et al. Activation of aryl hydrocarbon
receptor (AhR) in mesenchymal stem cells modulates macrophage polarization in
asthma. J Immunotoxicol (2020) 17(1):21–30. doi: 10.1080/1547691X.2019.1706 671
97. van Voorhis M, Knopp S, Julliard W, Fechner JH, Zhang X, Schauer JJ, et al.
Exposure to atmospheric particulate matter enhances Th17 polarization through
the aryl hydrocarbon receptor. PloS One (2013) 8(12):e82545. doi: 10.1371/
journal.pone.0082545
98. Sun L, Fu J, Lin SH, Sun JL, Xia L, Lin CH, et al. Particulate matter of 2.5 mm
or less in diameter disturbs the balance of T(H)17/regulatory T cells by targeting
glutamate oxaloacetate transaminase 1 and hypoxia-inducible factor 1ain an
asthma model. J Allergy Clin Immunol (2020) 145 (1):402–14. doi: 10.1016/
j.jaci.2019.10.008
99. Schulz VJ, Smit JJ, Huijgen V, Bol-Schoenmakers M, van Roest M, Kruijssen
LJ, et al. Non-dioxin-like AhR ligands in a mouse peanut allergy model. Toxicol Sci
(2012) 128(1):92–102. doi: 10.1093/toxsci/kfs131
100. Hammerschmidt-Kamper C, Biljes D, Merches K, Steiner I, Daldrup T,
Bol-Schoenmakers M, et al. Indole-3-carbinol, a plant nutrient and AhR-ligand
precursor, supports oral tolerance against OVA and improves peanut allergy
symptoms in mice. PloS One (2017) 12(6):e0180321. doi: 10.1371/journal.
pone.0180321
101. Esser C, Rannug A. The aryl hydrocarbon receptor in barrier organ
physiology, immunology, and toxicology. Pharmacol Rev (2015) 67(2):259–79.
doi: 10.1124/pr.114.009001
102. Fernandez-Salguero P, Pineau T, Hilbert DM, McPhail T, Lee SS, Kimura
S, et al. Immune system impairment and hepatic fibrosis in mice lacking the dioxin-
binding ah receptor. Science (1995) 268(5211):722–6. doi: 10.1126/science.7732381
103.SchmidtJV,SuGH,ReddyJK,SimonMC,Bradfield CA, et al.
Characterization of a murine ahr null allele: involvement of the ah receptor in
hepatic growth and development. Proc Natl Acad Sci U.S.A. (1996) 93(13):6731–6.
doi: 10.1073/pnas.93.13.6731
104. Andreola F, Fernandez-Salguero PM, Chiantore MV, Petkovich MP,
Gonzalez FJ, De Luca LM, et al. Aryl hydrocarbon receptor knockout mice
(AHR-/-) exhibit liver retinoid accumulation and reduced retinoic acid
metabolism. Cancer Res (1997) 57(14):2835–8.
105. Di Meglio P, Duarte JH, Ahlfors H, Owens ND, Li Y, Villanova F, et al.
Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory
skin conditions. Immunity (2014) 40(6):989–1001. doi: 10.1016/j.immuni.
2014.04.019
106. Yu J, Luo Y, Zhu Z, Zhou Y, Sun L, Gao J, Sun J, et al, et al. A tryptophan
metabolite of the skin microbiota attenuates inflammation in patients with atopic
dermatitis through the aryl hydrocarbon receptor. J Allergy Clin Immunol (2019)
143(6):2108–2119.e12. doi: 10.1016/j.jaci.2018.11.036
107. Fernandez-Salguero PM, Hilbert DM, Rudikoff S, Ward JM, Gonzalez FJ,
et al. Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-
tetrachlorodibenzo-p-dioxin-induced toxicity. Toxicol Appl Pharmacol (1 996)
140(1):173–9. doi: 10.1006/taap.1996.0210
108. Zou QY, Hong SL, Kang HY, Ke X, Wang XQ, Li J, et al. Effect of di-(2-
ethylhexyl) phthalate (DEHP) on allergic rhinitis. Sci Rep (2020) 10(1):14625.
doi: 10.1038/s41598-020-71517-6
109. Grishanova AY, Perepechaeva ML. Aryl hydrocarbon receptor in oxidative
stress as a double agent and its biological and therapeutic significance. Int J Mol Sci
(2022) 23(12):6719. doi: 10.3390/ijms23126719
110. Lee WJ,Liu SH,Chiang CK, LinSY, Liang KW, Chen CH, et al. Aryl hydrocarbon
receptor deficiency attenuates oxidative stress-related mesangial cell activation and
macrophage infiltration and extracellular matrix accumulation in diabetic nephropathy.
Antioxid Redox Signal (2016) 24(4):217–31. doi: 10.1089/ars.2015.6310
111. Qiu J, Heller JJ, Guo X, Chen ZM, Fish K, Fu YX, et al. The aryl
hydrocarbon receptor regulates gut immunity through modulation of innate
lymphoid cells. Immunity (2012) 36(1):92–104. doi: 10.1016/j.immuni.2011.11.011
112. Beamer CA, Shepherd DM. Role of the aryl hydrocarbon receptor (AhR) in
lung inflammation. Semin Immunopathol (2013) 35(6):693–704. doi: 10.1007/
s00281-013-0391-7
113. Kawasaki H, Chang HW, Tseng HC, Hsu SC, Yang SJ, Hung CH, et al. A
tryptophan metabolite, kynurenine, promotes mast cell activation through aryl
hydrocarbon receptor. Allergy (2014) 69(4):445–52. doi: 10.1111/all.12346
114. Nguyen NT, Kimura A, Nakahama T, Chinen I, Masuda K, Nohara K, et al.
Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a
kynurenine-dependent mechanism. Proc Natl Acad Sci U.S.A. (2010) 107
(46):19961–6. doi: 10.1073/pnas.1014465107
115. Mascanfroni ID, Takenaka MC, Yeste A, Patel B, Wu Y, Kenison JE, et al.
Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-a.
Nat Med (2015) 21(6):638–46. doi: 10.1038/nm.3868
116. Takami M, Fujimaki K, Nishimura MI, Iwashima M. Cutting edge: AhR is
a molecular target of calcitriol in human T cells. J Immunol (2015) 195(6):2520–3.
doi: 10.4049/jimmunol.1500344
117. Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR, Grigorieva EF,
et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon
receptor activation. Cell (2011) 147(3):629–40. doi: 10.1016/j.cell.2011.09.025
118. Xiong L, Dean JW, Fu Z, Oliff KN, Bostick JW, Ye J, et al. Ahr-Foxp3-
RORgt axis controls gut homing of CD4(+) T cells by regulating GPR15. Sci
Immunol (2020) 5(48):eaaz7277. doi: 10.1126/sciimmunol.aaz7277
119. Kadow S, Jux B, Zahner SP, Wingerath B, Chmill S, Clausen BE, et al. Aryl
hydrocarbon receptor is critical for homeostasis of invariant gammadelta T cells in
the murine epidermis. J Immunol (2011) 187(6):3104–10. doi: 10.4049/
jimmunol.1100912
120. Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC,
et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to
environmental toxins. Nature (2008) 453(7191):106–9. doi: 10.1038/nature06881
121. Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, et al.
Control of t(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor.
Nature (2008) 453(7191):65–71. doi: 10.1038/nature06880
Riaz et al. 10.3389/fimmu.2022.1057555
Frontiers in Immunology frontiersin.org14

122. Kiss EA, Vonarbourg C, Kopfmann S, Hobeika E, Finke D, Esser C, et al.
Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal
lymphoid follicles. Science (2011) 334(6062):1561–5. doi: 10.1126/science.1214914
123. Kanagaratham C, El Ansari YS, Lewis OL, Oettgen HC. IgE and IgG
antibodies as regulators of mast cell and basophil functions in food allergy. Front
Immunol (2020) 11:603050. doi: 10.3389/fimmu.2020.603050
124. Mendez-Enrı

quez E, Hallgren J. Mast cells and their progenitors in allergic
asthma. Front Immunol (2019) 10:821. doi: 10.3389/fimmu.2019.00821
125. Mukai K, Tsai M, Saito H, Galli SJ. Mast cells as sources of cytokines,
chemokines, and growth factors. Immunol Rev (2018) 282(1):121–50. doi: 10.1111/
imr.12634
126. DiNatale BC, Schroeder JC, Francey LJ, Kusnadi A, Perdew GH.
Mechanistic insights into the events that lead to synergistic induction of
interleukin 6 transcription upon activation of the aryl hydrocarbon receptor and
inflammatory signaling. J Biol Chem (2010) 285(32):24388–97. doi: 10.10 74/
jbc.M110.118570
127. Maaetoft-Udsen K, Shimoda LM, Frøkiær H, Turner H. Aryl hydrocarbon
receptor ligand effects in RBL2H3 cells. J Immunotoxicol (2012) 9(3):327–37. doi:
10.3109/1547691X.2012.661802
128. Swindle EJ, Metcalfe DD. The role of reactive oxygen species and nitric
oxide in mast cell-dependent inflammatory processes. Immunol Rev (2007)
217:186–205. doi: 10.1111/j.1600-065X.2007.00513.x
129. Wang H, Do DC, Liu J, Wang B, Qu J, Ke X, et al. Functional role of
kynurenine and aryl hydrocarbon receptor axis in chronic rhinosinusitis with nasal
polyps. J Allergy Clin Immunol (2018) 141(2):586–600.e6. doi: 10.1016/j.jaci.
2017.06.013
130. James B, Milstien S, Spiegel S. ORMDL3 and allergic asthma: From
physiology to pathology. J Allergy Clin Immunol (2019) 144(3):634–40. doi:
10.1016/j.jaci.2019.07.023
131. Wang HC, Wong TH, Wang LT, Su HH, Yu HY, Wu AH, et al. Aryl
hydrocarbon receptor signaling promotes ORMDL3-dependent generation of
sphingosine-1-phosphate by inhibiting sphingosine-1-phosphate lyase. Cell Mol
Immunol (2019) 16(10):783–90. doi: 10.1038/s41423-018-0022-2
132. Janssen-Weets B, Kerff F, Swiontek K, Kler S, Czolk R, Revets D, et al.
Mammalian derived lipocalin and secretoglobin respiratory allergens strongly bind
ligands with potentially immune modulating properties. Front Allergy (2022)
3:958711. doi: 10.3389/falgy.2022.958711
133. Roth-Walter F, Afify SM, Pacios LF, Blokhuis BR, Redegeld F, Regner A,
et al. Cow's milk protein b-lactoglobulin confers resilience against allergy by
targeting complexed iron into immune cells. J Allergy Clin Immunol (2021) 147
(1):321–334.e4. doi: 10.1016/j.jaci.2020.05.023
134. Humeniuk P, Dubiela P, Hoffmann-Sommergruber K. Dendritic cells and
their role in allergy: Uptake, proteolytic processing and presentation of allergens.
Int J Mol Sci (2017) 18(7):1491. doi: 10.3390/ijms18071491
135. Ruiter B, Shreffler WG. The role of dendritic cells in food allergy. J Allergy
Clin Immunol (2012) 129(4):921–8. doi: 10.1016/j.jaci.2012.01.080
136. Rowden G, Lewis MG, Sullivan AK. Ia antigen expression on human
epidermal langerhans cells. Nature (1977) 268(5617):247–8. doi: 10.1038/268247a0
137. Stingl G, Wolff-Schreiner EC, Pichler WJ, Gschnait F, Knapp W, Wolff K.
Epidermal langerhans cells bear fc and C3 receptors. Nature (1977) 268(5617):245–
6. doi: 10.1038/268245a0
138. Merad M, Ginhoux F, Collin M. Origin, homeostasis and function of
langerhans cells and other langerin-expressing dendritic cells. Nat Rev Immunol
(2008) 8(12):935–47. doi: 10.1038/nri2455
139. Aiba S, Tagami H. Dendritic cells play a crucial role in innate immunity to
simple chemicals. J Investig Dermatol Symp Proc (1999) 4(2):158–63. doi: 10.1038/
sj.jidsp.5640201
140. Serbina NV, Salazar-Mather TP, Biron CA, Kuziel WA, Pamer EG. TNF/
iNOS-producing dendritic cells mediate innate immune defense against bacterial
infection. Immunity (2003) 19(1):59–70. doi: 10.1016/S1074-7613(03)00171-7
141. Wollenberg A, Wagner M, Günther S, Towarowski A, Tuma E, Moderer
M, et al. Plasmacytoid dendritic cells: a new cutaneous dendritic cell subset with
distinct role in inflammatory skin diseases. J Invest Dermatol (2002) 119(5):1096–
102. doi: 10.1046/j.1523-1747.2002.19515.x
142. Stary G, Bangert C, Stingl G, Kopp T. Dendritic cells in atopic dermatitis:
expression of FcepsilonRI on two distinct inflammation-associated subsets. Int
Arch Allergy Immunol (2005) 138(4):278–90. doi: 10.1159/000088865
143. Wollenberg A, Mommaas M, Oppel T, Schottdorf EM, Günther S,
Moderer M, et al. Expression and function of the mannose receptor CD206 on
epidermal dendritic cells in inflammatory skin diseases. J Invest Dermatol (2002)
118(2):327–34. doi: 10.1046/j.0022-202x.2001.01665.x
144. Bieber T, Kraft S, Geiger E, Wollenberg A, Koch S, Novak N, et al. Fc
[correction of ec] epsilon RI expressing dendritic cells: the missing link in the
pathophysiology of atopic dermatitis? JDermatol(2000) 27(11):698–9.
doi: 10.1111/j.1346-8138.2000.tb02261.x
145. Smit JJ, Bol-Schoenmakers M, Hassing I, Fiechter D, Boon L, Bleumink R,
et al. The role of intestinal dendritic cells subsets in the establishment of food
allergy. Clin Exp Allergy (2011) 41(6):890–8. doi: 10.1111/j.1365-2222.2011.03738.x
146. Coombes JL, Siddiqui KR, Arancibia -Carcamo CV, Hall J, Sun CM,
Belkaid Y, et al. A functionally specialized population of mucosal CD103+ DCs
induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent
mechanism. J Exp Med (2007) 204(8):1757–64. doi: 10.1084/jem.20070590
147. Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, et al. Small
intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg
cells via retinoic acid. JExpMed(2007) 204(8):1775–85. doi: 10.1084/
jem.20070602
148. Coombes JL, Powrie F. Dendritic cells in intestinal immune regulation. Nat
Rev Immunol (2008) 8(6):435–46. doi: 10.1038/nri2335
149. van Wijk F, Wehrens EJ, Nierkens S, Boon L, Kasran A, Pieters R, et al.
CD4+CD25+ T cells regulate the intensity of hypersensitivity responses to peanut,
but are not decisive in the induction of oral sensitization. Clin Exp Allergy (2007) 37
(4):572–81. doi: 10.1111/j.1365-2222.2007.02681.x
150. Goudot C, Coillard A, Villani AC, Gueguen P, Cros A, Sarkizova S, et al.
Aryl hydrocarbon receptor controls monocyte differentiation into dendritic cells
versus macrophages. Immunity (2017) 47(3):582–596.e6. doi: 10.1016/
j.immuni.2017.08.016
151. Chmill S, Kadow S, Winter M, Weighardt H, Esser C. 2,3,7,8-
tetrachlorodibenzo-p-dioxin impairs stable establishment of oral tolerance in
mice. Toxicol Sci (2010) 118(1):98–107. doi: 10.1093/toxsci/kfq232
152. Bankoti J, Burnett A, Navarro S, Miller AK, Rase B, Shepherd DM, et al.
Effects of TCDD on the fate of naive dendritic cells. Toxicol Sci (2010) 115(2):422–
34. doi: 10.1093/toxsci/kfq063
153. Quintana FJ, Murugaiyan G, Farez MF, Mitsdoerffer M, Tukpah AM,
Burns EJ, et al. An endogenous aryl hydrocarbon receptor ligand acts on dendritic
cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc
Natl Acad Sci U.S.A. (2010) 107(48):20768–73. doi: 10.1073/pnas.1009201107
154. Jaronen M, Quintana FJ. Immunological relevance of the coevolution of
IDO1 and AHR. Front Immunol (2014) 5:521. doi: 10.3389/fimmu.2014.00521
155. Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield
CA, et al. An interaction between kynurenine and the aryl hydrocarbon receptor
can generate regulatory T cells. J Immunol (2010) 185(6):3190–8. doi: 10.4049/
jimmunol.0903670
156. Jux B, Kadow S, Esser C. Langerhans cell maturation and contact
hypersensitivity are impaired in aryl hydrocarbon receptor-null mice. J Immunol
(2009) 182(11):6709–17. doi: 10.4049/jimmunol.0713344
157. Vogel CF, Goth SR, Dong B, Pessah IN, Matsumura F. Aryl hydrocarbon
receptor signaling mediates expression of indoleamine 2,3-dioxygenase. Biochem
Biophys Res Commun (2008) 375(3):331–5. doi: 10.1016/j.bbrc.2008.07.156
158. Ross EA, Devitt A, Johnson JR. Macrophages: The good, the bad, and the
gluttony. Front Immunol (2021) 12:708186. doi: 10.3389/fimmu.2021.708186
159. Saradna A, Do DC, Kumar S, Fu QL, Gao P. Macrophage polarization and
allergic asthma. Transl Res (2018) 191:1–14. doi: 10.1016/j.trsl.2017.09.002
160. Mills CD. M1 and M2 macrophages: Oracles of health and disease. Crit Rev
Immunol (2012) 32(6):463–88. doi: 10.1615/CritRevImmunol.v32.i6.10
161. Suzuki K, Meguro K, Nakagomi D, Nakajima H. Roles of alternatively
activated M2 macrophages in allergic contact dermatitis. Allergol Int (2017) 66
(3):392–7. doi: 10.1016/j.alit.2017.02.015
162. Iwasaki N, Terawaki S, Shimizu K, Oikawa D, Sakamoto H, Sunami K, et al.
Th2 cells and macrophages cooperatively induce allergic inflammation through
histamine signaling. PloS One (2021) 16(3):e0248158. doi: 10.1371/
journal.pone.0248158
163. Girodet PO, Nguyen D, Mancini JD, Hundal M, Zhou X, Israel E, et al.
Alternative macrophage activation is increased in asthma. Am J Respir Cell Mol Biol
(2016) 55(4):467–75. doi: 10.1165/rcmb.2015-0295OC
164. Zhu J, Luo L, Tian L, Yin S, Ma X, Cheng S, et al. Aryl hydrocarbon
receptor promotes IL-10 expression in inflammatory macrophages through src-
STAT3 signaling pathway. Front Immunol (2018) 9. doi: 10.3389/
fimmu.2018.02033
165. Großkopf H, Walter K, Karkossa I, von Bergen M, Schubert K. Non-
genomic AhR-signaling modulates the immune response in endotoxin-activated
macrophages after activation by the environmental stressor BaP. Front Immunol
(2021) 12. doi: 10.3389/fimmu.2021.620270
166. Climaco-Arvizu S, Domı

nguez-Acosta O, Cabañas-Cortes MA, Rodrı

guez-
Sosa M, Gonzalez FJ, Vega L, et al. Aryl hydrocarbon receptor influences nitric
oxide and arginine production and alters M1/M2 macrophage polarization. Life Sci
(2016) 155:76–84. doi: 10.1016/j.lfs.2016.05.001
Riaz et al. 10.3389/fimmu.2022.1057555
Frontiers in Immunology frontiersin.org15

167. Hezaveh K, Shinde RS, Klötgen A, Halaby MJ, Lamorte S, Ciudad MT,
et al. Tryptophan-derived microbial metabolites activate the aryl hydrocarbon
receptor in tumor-associated macrophages to suppress anti-tumor immunity.
Immunity (2022) 55(2):324–340.e8. doi: 10.1016/j.immuni.2022.01.006
168. Riemschneider S, Kohlschmidt J, Fueldner C, Esser C, Hauschildt S,
Lehmann J, et al. Aryl hydrocarbon receptor activation by benzo(a)pyrene
inhibits proliferation of myeloid precursor cells and alters the differentiation
state as well as the functional phenotype of murine bone marrow-derived
macrophages. Toxicol Lett (2018) 296:106–13. doi: 10.1016/j.toxlet.2018.07.050
169. Yang X, Liu H, Ye T, Duan C, Lv P, Wu X, et al. AhR activation attenuates
calcium oxalate nephrocalcinosis by diminishing M1 macrophage polarization and
promoting M2 macrophage polarization. Theranostics (2020) 10(26):12011–25.
doi: 10.7150/thno.51144
170. Shinde R, Hezaveh K, Halaby MJ, Kloetgen A, Chakravarthy A, da Silva
Medina T, et al. Apoptotic cell-induced AhR activity is required for immunological
tolerance and suppression of systemic lupus erythematosus in mice and humans.
Nat Immunol (2018) 19(6):571–82. doi: 10.1038/s41590-018-0107-1
171. Cancro MP, Tomayko MM. Memory b cells and plasma cells: The
differentiative continuum of humoral immunity. Immunol Rev (2021) 303(1):72–
82. doi: 10.1111/imr.13016
172. Ettmayer P, Mayer P, Kalthoff F, Neruda W, Harrer N, Hartmann G, et al.
A novel low molecular weight inhibitor of dendritic cells and b cells blocks allergic
inflammation. Am J Respir Crit Care Med (2006) 173(6):599–606. doi: 10.1164/
rccm.200503-468OC
173. Vaidyanathan B, Chaudhry A, Yewdell WT, Angeletti D, Yen WF,
Wheatley AK, et al. The aryl hydrocarbon receptor controls cell-fate decisions in
b cells. J Exp Med (2017) 214(1):197–208. doi: 10.1084/jem.20160789
174. Piper CJM, Rosser EC, Oleinika K, Nistala K, Krausgruber T, Rendeiro AF,
et al. Aryl hydrocarbon receptor contributes to the transcriptional program of IL-
10-Producing regulatory b cells. Cell Rep (2019) 29(7):1878–1892.e7. doi: 10.1016/
j.celrep.2019.10.018
175. Rosser EC, Piper CJM, Matei DE, Blair PA, Rendeiro AF, Orford M, et al.
Microbiota-derived metabolites suppress arthritis by amplifying aryl-hydrocarbon
receptor activation in regulatory b cells. Cell Metab (2020) 31(4):837–851.e10. doi:
10.1016/j.cmet.2020.03.003
176. Kerkvliet NI. Recent advances in understanding the mechanisms of TCDD
immunotoxicity. Int Immunopharmacol (2002) 2(2-3):277–91. doi: 10.1016/S1567-
5769(01)00179-5
177. Sulentic CE, Kaminski NE. The long winding road toward understanding
the molecular mechanisms for b-cell suppression by 2,3,7,8-tetrachlorodibenzo-p-
dioxin. Toxicol Sci (2011) 120 Suppl 1(Suppl 1):S171–91. doi: 10.1093/toxsci/
kfq324
178. Lambrecht BN, Hammad H. The immunology of the allergy epidemic and
the hygiene hypothesis. Nat Immunol (2017) 18(10):1076–83. doi: 10.1038/ni.3829
179. Robinson DS, Hamid Q, Ying S, Tsicopoulos A, Barkans J, Bentley AM, et al.
Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N
Engl J Med (1992) 326(5):298–304. doi: 10.1056/NEJM199201303260504
180. McKenzie AN. Type-2 innate lymphoid cells in asthma and allergy. Ann
Am Thorac Soc (2014) 11 Suppl 5(Suppl 5):S263–70. doi: 10.1513/
AnnalsATS.201403-097AW
181. Everaere L, Ait-Yahia S, Molendi-Coste O, Vorng H, Quemener S, LeVu P,
et al. Innate lymphoid cells contribute to allergic airway disease exacerbation by
obesity. J Allergy Clin Immunol (2016) 138(5):1309–1318.e11. doi: 10.1016/
j.jaci.2016.03.019
182. Kim HY, Lee HJ, Chang YJ, Pichavant M, Shore SA, Fitzgerald KA, et al.
Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome
facilitate obesity-associated airway hyperreactivity. Nat Med (2014) 20(1):54–61.
doi: 10.1038/nm.3423
183. Lee JS, Lee HJ, Chang YJ, Pichavant M, Shore SA, Fitzgerald KA, et al. AHR
drives the development of gut ILC22 cells and postnatal lymphoid tissues via
pathways dependent on and independent of notch. Nat Immunol (2011) 13
(2):144–51. doi: 10.1038/ni.2187
184. Li S, Cella M, McDonald KG, Garlanda C, Kennedy GD, Nukaya M, et al.
Aryl hydrocarbon receptor signaling cell intrinsically inhibits intestinal group 2
innate lymphoid cell function. Immunity (2018) 49(5):915–928.e5. doi: 10.1016/
j.immuni.2018.09.015
185. Stockinger B, Di Meglio P, Gialitakis M, Duarte JH. The aryl hydrocarbon
receptor: multitasking in the immune system. Annu Rev Immunol (2014) 32:403–
32. doi: 10.1146/annurev-immunol-032713-120245
186. Kimura A, Naka T, Nohara K, Fujii-Kuriyama Y, Kishimoto T, et al. Aryl
hydrocarbon receptor regulates Stat1 activation and participates in the
development of Th17 cells. Proc Natl Acad Sci U.S.A. (2008) 105(28):9721–6.
doi: 10.1073/pnas.0804231105
187. PleC, Fan Y, Ait Yahia S, Vorng H, Everaere L, Chenivesse C, et al.
Polycyclic aromatic hydrocarbons reciprocally regulate IL-22 and IL-17 cytokines
in peripheral blood mononuclear cells from both healthy and asthmatic subjects.
PloS One (2015) 10(4):e0122372. doi: 10.1371/journal.pone.0122372
188. Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H. Identification of a
human helper T cell population that has abundant production of interleukin 22
and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat Immunol (2009) 10
(8):864–71. doi: 10.1038/ni.1770
189. Lee Y, Awasthi A, Yosef N, Quintana FJ, Xiao S, Peters A, et al. Induction
and molecular signature of pathogenic TH17 cells. Nat Immunol (2012) 13
(10):991–9. doi: 10.1038/ni.2416
190. Funatake CJ, Marshall NB, Steppan LB, Mourich DV, Kerkvliet NI. Cutting
edge: activation of the aryl hydrocarbon receptor by 2,3,7,8-tetrachlorodibenzo-p-
dioxin generates a population of CD4+ CD25+ cells with characteristics of regulatory
T cells. J Immunol (2005) 175(7):4184–8. doi: 10.4049/jimmunol.175.7.4184
191. Gandhi R, Kumar D, Burns EJ, Nadeau M, Dake B, Laroni A, et al.
Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T
cell-like and Foxp3(+) regulatory T cells. Nat Immunol (2010) 11(9):846–53. doi:
10.1038/ni.1915
192. Singh NP, Singh UP, Singh B, Price RL, Nagarkatti M, Nagarkatti PS, et al.
Activation of aryl hydrocarbon receptor (AhR) leads to reciprocal epigenetic
regulation of FoxP3 and IL-17 expression and amelioration of experimental
colitis. PloS One (2011) 6(8):e23522. doi: 10.1371/journal.pone.0023522
193. Suarez-Alvarez B, Rodriguez RM, Fraga MF, Lopez-Larrea C. DNA
Methylation: a promising landscape for immune system-related diseases. Trends
Genet (2012) 28(10):506–14. doi: 10.1016/j.tig.2012.06.005
194. Nadeau K, McDonald-Hyman C, Noth EM, Pratt B, Hammond SK,
Balmes J, et al. Ambient air pollution impairs regulatory T-cell function in
asthma. J Allergy Clin Immunol (2010) 126(4):845–852.e10. doi: 10.1016/
j.jaci.2010.08.008
195. Apetoh L, Quintana FJ, Pot C, Joller N, Xiao S, Kumar D, et al. The aryl
hydrocarbon receptor interacts with c-maf to promote the differentiation of type 1
regulatory T cells induced by IL-27. Nat Immunol (2010) 11(9):854–61. doi:
10.1038/ni.1912
196. Tousa S, Semitekolou M, Morianos I, Banos A, Trochoutsou AI, Brodie
TM, et al. Activin-a co-opts IRF4 and AhR signaling to induce human regulatory T
cells that restrain asthmatic responses. Proc Natl Acad Sci U.S.A. (2017) 114(14):
E2891–e2900. doi: 10.1073/pnas.1616942114
197. Gagliani N, Amezcua Vesely MC, Iseppon A, Brockmann L, Xu H, Palm
NW, et al. Th17 cells transdifferentiate into regulatory T cells during resolution of
inflammation. Nature (2015) 523(7559):221–5. doi: 10.1038/nature14452
198. Wei P, Hu GH, Kang HY, Yao HB, Kou W, Liu H, et al. An aryl
hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress the
Th17 response in allergic rhinitis patients. Lab Invest (2014) 94(5):528–35. doi:
10.1038/labinvest.2014.8
199. Quintana FJ, Jin H, Burns EJ, Nadeau M, Yeste A, Kumar D, et al. Aiolos
promotes TH17 differentiation by directly silencing Il2 expression. Nat Immunol
(2012) 13(8):770–7. doi: 10.1038/ni.2363
200. Wang J, Zhao Y, Zhang X, Tu W, Wan R, Shen Y, et al. Type II alveolar
epithelial cell aryl hydrocarbon receptor protects against allergic airway
inflammation through controlling cell autophagy. Front Immunol (2022)
13:964575. doi: 10.3389/fimmu.2022.964575
201. Basu R, O'Quinn DB, Silberger DJ, Schoeb TR, Fouser L, Ouyang W, et al.
Th22 cells are an important source of IL-22 for host protection against
enteropathogenic bacteria. Immunity (2012) 37(6):1061–75. doi: 10.1016/
j.immuni.2012.08.024
202. Ramirez JM, Brembilla NC, Sorg O, Chicheportiche R, Matthes T, Dayer
JM, et al. Activation of the aryl hydrocarbon receptor reveals distinct requirements
for IL-22 and IL-17 production by human T helper cells. Eur J Immunol (2010) 40
(9):2450–9. doi: 10.1002/eji.201040461
203. Lawrence BP, Roberts AD, Neumiller JJ, Cundiff JA, Woodland DL, et al.
Aryl hydrocarbon receptor activation impairs the priming but not the recall of
influenza virus-specific CD8+ T cells in the lung. J Immunol (2006) 177(9):5819–
28. doi: 10.4049/jimmunol.177.9.5819
204. Winans B, Nagari A, Chae M, Post CM, Ko CI, Puga A, et al. Linking the
aryl hydrocarbon receptor with altered DNA methylation patterns and
developmentally induced aberrant antiviral CD8+ T cell responses. J Immunol
(2015) 194(9):4446–57. doi: 10.4049/jimmunol.1402044
205. Zaid A, Mackay LK, Rahimpour A, Braun A, Veldhoen M, Carbone FR,
et al. Persistence of skin-resident memory T cells within an epidermal niche. Proc
Natl Acad Sci U.S.A. (2014) 111(14):5307–12. doi: 10.1073/pnas.1322292111
206. Lockhart E, Green AM, Flynn JL. IL-17 production is dominated by
gammadelta T cells rather than CD4 T cells during mycobacterium tuberculosis
infection. J Immunol (2006) 177(7):4662–9. doi: 10.4049/jimmunol.177.7.4662
207. Duan J, Chung H, Troy E, Kasper DL. Microbial colonization drives
expansion of IL-1 receptor 1-expressing and IL-17-producing gamma/delta T cells.
Cell Host Microbe (2010) 7(2):140–50. doi: 10.1016/j.chom.2010.01.005
Riaz et al. 10.3389/fimmu.2022.1057555
Frontiers in Immunology frontiersin.org16

208. Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M. Interleukin-17-
producing gammadelta T cells selectively expand in response to pathogen products
and environmental signals. Immunity (2009) 31(2):321–30. doi: 10.1016/
j.immuni.2009.06.020
209. Schulz VJ, Smit JJ, Bol-Schoenmakers M, van Duursen MB, van den Berg M,
Pieters RH, et al. Activation of the aryl hydrocarbon receptor reduces the number of
precursorand effector T cells, but preservesthymic CD4+CD25+Foxp3+ regulatory T
cells. Toxicol Lett (2012) 215(2):100–9. doi: 10.1016/j.toxlet.2012.09.024
210. Vuerich M, Harshe R, Frank LA, Mukherjee S, Gromova B, Csizmadia E,
et al. Altered aryl-hydrocarbon-receptor signalling affects regulatory and effector
cell immunity in autoimmune hepatitis. J Hepatol (2021) 74(1):48–57. doi: 10.1016/
j.jhep.2020.06.044
211. Kamanaka M, Huber S, Zenewicz LA, Gagliani N, Rathinam C, O'Connor
Jr W, et al. Memory/effector (CD45RB(lo)) CD4 T cells are controlled directly by
IL-10 and cause IL-22-dependent intestinal pathology. J Exp Med (2011) 208
(5):1027–40. doi: 10.1084/jem.20102149
212. Kirchberger S, RoystonDJ, Boulard O, Thornton E, Franchini F, Szabady RL,
et al. Innate lymphoid cells sustain colon cancer through production of interleukin-22
in a mouse model. J Exp Med (2013) 210(5):917–31. doi: 10.1084/jem.20122308
213. Robbins K, Bissonnette R, Maeda-Chubachi T, Ye L, Peppers J, Gallagher
K, et al. Phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream)
for the treatment of plaque psoriasis. J Am Acad Dermatol (2019) 80(3):714–21.
doi: 10.1016/j.jaad.2018.10.037
214. Kaye J, Piryatinsky V, Birnberg T, Hingaly T, Raymond E, Kashi R, et al.
Laquinimod arrests experimental autoimmune encephalomyelitis by activating the
aryl hydrocarbon receptor. Proc Natl Acad Sci U.S.A. (2016) 113(41):E6145–e6152.
doi: 10.1073/pnas.1607843113
215. Smith SH, Jayawickreme C, Rickard DJ, Nicodeme E, Bui T, Simmons C,
et al. Tapinarof is a natural AhR agonist that resolves skin inflammation in mice
and humans. JInvestDermatol(2017) 137(10):2110–9. doi: 10.1016/j.jid.
2017.05.004
216. Wang HC, Huang SK. Metformin inhibits IgE- and aryl hydrocarbon
receptor-mediated mast cell activation in vitro and in vivo. Eur J Immunol (2018)
48(12):1989–96. doi: 10.1002/eji.201847706
217. Mays LE, Ammon-Treiber S, Mothes B, Alkhaled M, Rottenberger J,
Müller-Hermelink ES, et al. Modified Foxp3 mRNA protects against asthma
through an IL-10-dependent mechanism. J Clin Invest (2013) 123(3):1216–28.
doi: 10.1172/JCI65351
Riaz et al. 10.3389/fimmu.2022.1057555
Frontiers in Immunology frontiersin.org17