Content uploaded by Renqi Yao
Author content
All content in this area was uploaded by Renqi Yao on May 30, 2024
Content may be subject to copyright.
Open Access
© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits
use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original
author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third
party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the mate‑
rial. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or
exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://
creativecommons.org/licenses/by/4.0/.
MINI REVIEW
Zhengetal.
Cellular & Molecular Biology Letters (2024) 29:81
https://doi.org/10.1186/s11658-024-00602-9
Cellular & Molecular
Biology Letters
Dysregulated dendritic cells insepsis:
functional impairment andregulated cell death
Li‑yu Zheng1†, Yu Duan2†, Peng‑yi He1†, Meng‑yao Wu1, Shu‑ting Wei1, Xiao‑hui Du3*, Ren‑qi Yao1,3* and
Yong‑ming Yao1*
Abstract
Sepsis is defined as life‑threatening organ dysfunction caused by a dysregulated host
response to infection. Studies have indicated that immune dysfunction plays a central
role in the pathogenesis of sepsis. Dendritic cells (DCs) play a crucial role in the emer‑
gence of immune dysfunction in sepsis. The major manifestations of DCs in the septic
state are abnormal functions and depletion in numbers, which are linked to higher
mortality and vulnerability to secondary infections in sepsis. Apoptosis is the most
widely studied pathway of number reduction in DCs. In the past few years, there
has been a surge in studies focusing on regulated cell death (RCD). This emerging field
encompasses various forms of cell death, such as necroptosis, pyroptosis, ferropto‑
sis, and autophagy‑dependent cell death (ADCD). Regulation of DC’s RCD can serve
as a possible therapeutic focus for the treatment of sepsis. Throughout time, numer‑
ous tactics have been devised and effectively implemented to improve abnormal
immune response during sepsis progression, including modifying the functions of DCs
and inhibiting DC cell death. In this review, we provide an overview of the functional
impairment and RCD of DCs in septic states. Also, we highlight recent advances in tar‑
geting DCs to regulate host immune response following septic challenge.
Keywords: Sepsis, Dendritic cells, Functional impairment, Regulated cell death,
Immunomodulation
Graphical Abstract
†Li‑yu Zheng, Yu Duan and Peng‑
yi He have contributed equally to
this manuscript.
*Correspondence:
duxiaohui301@sina.com;
yaorenqixx1995@163.com;
c_ff@sina.com
1 Translational Medicine Research
Center, Medical Innovation
Research Division of the Chinese
PLA General Hospital, 28
Fuxing Road, Haidian District,
Beijing 100853, China
2 Department of Critical Care
Medicine, Affiliated Chenzhou
Hospital (the First People’s
Hospital of Chenzhou),
Southern Medical University,
Chenzhou 423000, China
3 Department of General
Surgery, The First Medical Center
of Chinese PLA General Hospital,
28 Fuxing Road, Haidian District,
Beijing 100853, China
Page 2 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
Introduction
According to the ird International Consensus Definition for Sepsis and Septic Shock
(Sepsis 3.0), sepsis is defined as life-threatening organ dysfunction caused by dysregu-
lated host responses to infection [1]. Sepsis is a major complication in patients admitted
to the medical intensive care unit (ICU) and has long been recognized as the primary
factor contributing to mortality in critically ill patients [2]. It possesses the character-
istics of high morbidity and mortality, along with frequent incidence of sequelae [3].
In line with the recently published epidemiological data, there are roughly 48.9 million
new sepsis cases, with more than 11 million deaths in the world annually [4]. In-hospi-
tal mortality of septic patients has declined over the past decades, attributed to earlier
recognition of sepsis and best-practices supportive therapies [5]. e pathophysiologi-
cal mechanisms underlying sepsis appear to be complicated, including imbalance of
inflammatory response, immunosuppression, coagulation disorders, etc. [3]. A compre-
hensive of the pathogenesis of sepsis holds significant theoretical importance and practi-
cal value in terms of its clinical diagnosis, treatment, and prognosis [6]. Recent findings
suggest that immune dysfunction is a crucial factor in the progression of sepsis, as the
majority of septic individuals have encountered instances of lymphopenia. However, the
specific mechanisms that cause sepsis-induced immunosuppression at the cellular and
molecular levels still need to be elucidated [7, 8]. To aid in our understanding of the
pathophysiological process of sepsis, it is significantly helpful to comprehend the altera-
tions in different immune cell subsets in the setting of sepsis. is knowledge can poten-
tially provide a therapeutic target for immune-modulatory strategies [9]. e aim of this
review is to investigate the potential involvement of dendritic cells (DCs) in sepsis, tak-
ing into account their significant impact on the host’s immune response.
DCs serve as proficient antigen-presenting cells (APCs), connecting innate immunity
with adaptive immunity. ey possess the ability to identify harmful microorganisms,
display antigens, trigger adaptive immunity, and promote the development of autoim-
mune immune tolerance. e involvement of DCs in the development of immune dys-
regulation after sepsis onset is widely recognized [10]. Specifically, DCs exhibit abnormal
functions and obviously decreased numbers in sepsis [11–13]. DCs can be divided into
several subsets based on location, ontogeny, and functions [14]. It is worth mentioning
that recent studies have discovered new categories of DCs through the use of advanced
techniques such as single-cell RNA sequencing (scRNA-seq) and cytometry by time-of-
flight (CytoF), which enable high-throughput analysis [15–17]. Studies have suggested
that previously neglected DC populations may be necessary for certain immunopatholo-
gies [18, 19]. Several studies have consistently reported that the decreases in DCs counts
are closely related to the elevated mortality rates and incidences of nosocomial infec-
tion among patients with sepsis [20–23]. Notably, a substantial reduction in DCs can
be primarily attributed to initiating a cell death program caused by sepsis. It was found
that DC reduction was mainly mediated by caspase-3-dependent apoptotic pathways,
whereas newly published studies revealed that the other forms of programmed cell
death (PCD) could contribute to the depletion of DCs in sepsis. Given the pathophysi-
ological significance of the reduction of DCs in pathogenesis and development of sepsis,
herein we summarized the recent advances in the PCD of DCs during sepsis, includ-
ing apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death
Page 3 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
(ADCD). Recent studies have shown that novel immunomodulatory interventions that
target DCs can reduce morbidity and mortality in sepsis and septic shock by modifying
the immune functions of DCs and inhibiting DC cell death [13, 22, 24–26]. Considering
the crucial function of DCs in the onset and advancement of sepsis, this review aims
to consolidate the research advancements on DCs in sepsis. It particularly focuses on
the emerging forms of PCD in DCs during septic exposure, aiming to enhance compre-
hension of the immune pathogenesis of sepsis and consequently offer new targets for
immunomodulation.
Classication ofDC subsets
DCs are a class of bone-marrow-originated cells differentiating from lymph-myeloid
hematopoietic stem cells. eir developmental trajectory depends on the synergetic
effect of transcription factors that facilitate lymph-myeloid differentiation [27, 28]. Since
each DC subset exerts a unique function, it is critical to understand the physiological
characteristics across disparate subsets of DCs [29]. DCs can be roughly categorized into
classical or conventional DCs (cDCs), plasmacytoid DCs (pDCs), and follicular dendritic
cells (FDCs) [27, 30–33] (Fig.1). cDCs originating from common myeloid progenitors
(CMPs) in bone marrow express high levels of CD11c and the major histocompatibility
complex (MHC)-II, making them the most potent APCs invivo. Corresponding to dif-
ferent phenotypic markers and functions, they can be further divided into two subsets:
cDC1 and cDC2. Phenotypically, cDC1s are characterized as high expression of CD141,
whereas upregulated CD1c is noted in cDC2s [29]. At the functional level, cDC1s rep-
resent critical players in anti-virus and anti-tumor immunity through cross-presenting
intracellular antigens to cytotoxic CD8+ T cells (CTLs) via MHC-I [32]. In contrast,
cDC2s possess a potent intrinsic capacity to present extracellular antigens, parasites, and
allergens to helper CD4+ T cells () through MHC-II expression [32, 34]. Langerhans
cells (LCs) are a specific type of cDC that mainly gathers in peripheral non-lymphoid
tissues. ese cDCs have a low level of MHC-II and costimulatory molecules, but they
have a high level of Toll-like receptors (TLRs), modulatory receptors, and chemokine
receptors. eir ability to absorb and process antigens is potent, whereas the capacity to
present antigens remains relatively weak [35]. pDCs are identified as CD11cdim CD123+,
derived from bone marrow common lymphoid progenitors (CLPs) [29]. pDCs have
a round plasma cell-like morphology and express intermediate levels of MHC-II and
costimulatory molecules, enabling pDCs to present antigens to CD4+ T cells. However,
they typically express a group of TLRs such as TLR7 and TLR9, which mainly recognize
microbial dsRNA, ssDNA, or bacterial/viral CpG DNA, rendering its key role in pre-
venting virus infection. Upon activation, it has the ability to release a significant quantity
of type I interferon (IFN-α/β) [32]. FDCs are developed from mesenchymal progenitor
cells (MPCs), distributed in lymph nodes, spleen, lymph follicles, and germinal centers
of the mucosal immune system [36]. FDCs lack the ability to present antigens owing to
the absence of MHC-II and costimulatory molecules. FDCs can effectively capture anti-
gen–antibody complex, antigen-complement complex, and antigen–antibody-comple-
ment complex through highly expressed IgG Fc receptor and C3b/C3d receptor [36–39].
FDCs attract B cells by producing and releasing CXC chemokine ligand (CXCL)13. e
B cells then efficiently recognize, ingest, and process the antigen or immune complex on
Page 4 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
Fig. 1 The fate of dendritic cells (DCs) during sepsis. The upper left panel shows the different subsets of
DCs in homeostasis conditions. The upper right panel shows the changes in DCs during sepsis, including
number reduction of normal subsets, alteration in subsets, and functional defects of altered subsets. The
lower panel shows three aspects of DC dysfunction in a septic state, including the expression of surface
molecules, cytokine secretion, and antigen presentation capacity. These changes will lead to the formation of
an immunosuppressive environment, which is closely associated with increased mortality and susceptibility
to secondary infections in patients with sepsis. DCs, dendritic cells; cDCs, classical or conventional DCs; pDCs,
plasmacytoid dendritic cells; FDCs, follicular dendritic cells; MHC, major histocompatibility complex; MHC‑II,
MHC class II; HLA‑DR, human leukocyte antigen‑DR; IL, interleukin; IFN, interferon; TNF, tumor necrosis factor;
TGF, transforming growth factor; Tregs, regulatory T cells; Th, T helper cells
Page 5 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
the FDCs’ surface [40, 41]. A group of mature DCs with an abundance of immunoregula-
tory molecules, referred to as “mature DCs enriched in immunoregulatory molecules”
(mregDCs), was recently discovered in non-small cell lung cancer through scRNA-seq
[19]. In our previous investigation, we examined the diversity of immune cell subsets in
a murine sepsis model using scRNA-seq. We observed a significant increase in spleen-
resident mregDCs shortly after the cecal ligation and puncture (CLP) procedure, indi-
cating their involvement in the hyperinflammatory phase of sepsis. Furthermore, the
existence of mregDCs in bronchoalveolar lavage fluid (BALF) of individuals with sepsis
was substantiated by utilizing up-to-date findings from a single-cell investigation of sub-
jects with COVID-19 [18].
The functional impairment ofDCs insepsis
e crucial involvement of DCs in the onset and progression of septic complications has
been widely acknowledged, as both the function of DCs and the total number of DCs
undergo significant alterations during sepsis. Many studies mainly focus on the func-
tions of DCs, of which three essential aspects can be characterized (Fig.1).
Surface molecular expression
Mature DCs become dysfunctional upon sustainable septic insults [46]. Functional
markers such as CD40, CD80, CD86, and MHC-II were significantly upregulated by
DCs in animal sepsis models during the initial phase of sepsis, which is essential for the
activation of T cells, while DCs downregulated the expression of surface molecules at
the late stage of sepsis [42]. Furthermore, clinical findings indicated that the presence of
HLA-DR on DCs was notably reduced in individuals suffering from sepsis, indicating its
crucial prognostic significance for patients experiencing immune suppression [12, 43].
Cytokine secretion
e cytokines secreted by DCs are obviously altered during sepsis [12, 44–46]. ere is
a proposal suggesting that the secretion pattern of cytokines in DCs is atypical in sep-
sis, leading to a significant decrease in the release of proinflammatory cytokines [tumor
necrosis factor (TNF)-α, IL-1β, and IL-12]. On the other hand, there is a significant
increase in the production of anti-inflammatory cytokines (such as TGF-β and IL-10),
showing similar characteristics to the endotoxin tolerance observed in monocytes [12,
42, 45, 47]. Human DCs treated with IL-10 exhibit suppressor activity specific to anti-
gens, thereby contributing to the development of anergic T cells [48]. TGF-β promotes
the accumulation of regulatory T cells (Tregs) in lung-induced immune paralysis and
forms an immunosuppressive environment in sepsis [23].
T cell‑stimulatory capacity
It has been demonstrated that the ability of DCs to stimulate T cells is significantly
diminished in cases of sepsis [49]. e proof of this can be seen in the decrease in T cell
growth, the lower production of cytokines like IL-2, and the higher IFN-γ/IL-4 ratio,
suggesting a change in T cell polarization toward the 2 pathway [50]. e production
of DCs by hematopoietic stem cells and hematopoietic progenitor cells (HSPCs) is hin-
dered by systemic inflammation caused by sepsis [51]. Furthermore, the makeup of DC
Page 6 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
subcategories experienced notable modifications [12]. e quantities of cDCs and pDCs
in the bloodstream of septic individuals decreased significantly, while the transformation
of monocytes into CD1a− DCs intensified, consequently inducing T cell anergy and fos-
tering Treg proliferation [52–54]. Furthermore, DCs can manifest as an immature state
upon septic challenge, which produce large amounts of IL-10 instead of IL-12, inducing
an anergic profile of T cells and a propensity toward Tregs [42, 54].
In the setting of sepsis, the mechanisms with regard to impaired functions of DCs
are largely unknown. Possible reasons for this could be linked to the following aspects.
Firstly, the endoplasmic reticulum stress (ERS) serves as an internal self-defense mecha-
nism. Moderate ERS is conducive to restoring cell homeostasis under external stimu-
lation; prolonged or excessive ERS impairs ER function, resulting in autophagy and/or
apoptosis. At the early stage of sepsis, the activation of ERS facilitates the maturation
and activation of DCs and promotes T cell proliferation and polarization toward 1. At
the late stage of sepsis, an overabundance of ERS may lead to apoptosis of DCs [55]. Sec-
ondly, newly discovered negative immunoregulatory proteins, such as tumor necrosis
factor α-induced protein 8 like-1 (TNFAIP8L2, TIPE1) and TIPE2 from tumor necrosis
factor α-induced protein 8 family, have been found to inhibit the maturation and activa-
tion of DCs in septic mice. Studies indicate that TIPE1 inhibits the maturation of DCs
and subsequent T-cell-mediated immunity via the programmed cell death-ligand 1 (PD-
L1)/programmed death 1 (PD-1) signaling pathway [56]. TIPE2 inhibits DC immune
function by suppressing autophagy through the TGF-β-activated kinase 1 (TAK1)/c-Jun
N-terminal kinases (JNK) pathway [57]. irdly, organelle-specific autophagy, which is a
significant subtype of autophagy, specifically aims to degrade various organelles in order
to maintain their quality. In sepsis, the dysfunction of DCs was prevented by regulat-
ing the quality control of mitochondria through protein tyrosine phosphatase (PTEN)-
induced putative kinase 1 (PINK1)-mediated mitophagy, as indicated by a report [58].
Regulated cell death ofDCs insepsis
Of note, another significant alteration is the decrease in the amount of DCs upon septic
challenge [24, 59–62]. Studies on animal models of sepsis and human sepsis have found
a marked depletion of DCs in lymphoid and non-lymphoid organs [9, 63–65]. In a study
using CLP mice, they noticed that the splenic CD11c+ DCs underwent evident apoptosis
through the caspase-3 pathway at 12–36h after the onset of sepsis, thereby resulting in
significantly decreased DC number in the abdominal cavity [59, 66–69]. e reduction
of DCs was directly related to the prognosis and the incidence of nosocomial infection
in patients [20, 22, 23]. Hence, keeping track of the quantity of DCs can offer an initial
valuable evaluation of the seriousness concerning the disruption of the host’s immune
response to infection, which could aid in forecasting fatal consequences in patients with
sepsis and offer a fresh approach for treating sepsis-induced immunosuppression [13,
22].
For the past 10years, the Nomenclature Committee on Cell Death (NCCD) has con-
sistently revised the categorization of cell death on the basis of morphological, biochem-
ical, and functional viewpoints [70]. Cell death is now classified into accidental cell death
(ACD) and RCD on the basis of functional status. ACD means the instantaneous and
catastrophic demise of cells exposed to severe physical, chemical, or mechanical insults.
Page 7 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
In stark opposition to ACD, RCD depends on specialized molecular apparatus, suggest-
ing that it can be influenced (i.e., postponed or expedited) through pharmacological or
genetic interventions. ACD is an uncontrolled biological process, while RCD consists
of well-organized signaling cascades and specific molecular effector mechanisms. RCD
under physiological conditions is also referred to as PCD. Currently known types of
RCD can be divided into several subtypes in terms of molecular basis, including apopto-
sis, necroptosis, pyroptosis, ferroptosis, ADCD, and so on.
Apoptosis
Apoptosis is the term used to describe genetically determined processes that selectively
remove unnecessary, permanently impaired, or potentially dangerous cells [71]. Apop-
totic death of immune cells has been extensively studied in sepsis, and it plays a crucial
role in immune hyporesponsiveness and even organ dysfunction [72]. As a bridge link-
ing innate immunity with adaptive immunity, apoptosis of DCs appears to be critically
involved in immunosuppression secondary to septic insults [44, 72, 73].
Numerous researchers have identified two primary routes of apoptosis: the intrinsic
pathway, also known as the mitochondrial pathway, and the extrinsic pathway, alterna-
tively referred to as the death receptor pathway. Intrinsic or mitochondrial pathways
can be triggered by stimuli mediated oxidative stress, mitochondrial disorder, and DNA
damage, including anti-tumor agents, hypoxia, ischemia–reperfusion injury, and ioniz-
ing radiation. Damage to the mitochondria results in increased permeability of the outer
membrane of the mitochondria, causing a significant release of cytochrome c into the
cytoplasm. is cytochrome c then binds with apoptotic protease activating factor-1
(APAF-1), initiating the cascade of apoptosis by activating pro-caspase 9 and forming
a complex known as the “apoptotic body.” Ligands binding to death receptors, such as
TNF–TNF receptor (TNFR)1, factor-associated suicide ligand (FasL)-factor-associated
suicide (Fas), and TNF-related apoptosis-inducing ligand (TRAIL)–TRAIL receptor
(TRAILR), induce extrinsic or death receptor pathways. e caspase protease family
mediates the convergence of internal and external pathways, resulting in the develop-
ment of characteristic apoptotic traits such as DNA fragmentation, chromatin conden-
sation, cell shrinkage, and membrane blistering. In addition, it is noteworthy that the
extrinsic pathway triggers intrinsic mitochondrial apoptosis by activating caspase-8.
Both intrinsic and extrinsic pathways can be influenced by signaling cascades, including
p53, nuclear factor κ-B (NF-κB), ubiquitin–proteasome system, and phosphoinositide
3 kinase (PI3K) pathways, indicating extensive crosstalk between these two apoptotic
pathways.
Since the apoptosis process of DCs is largely context dependent concerning different
stimuli, we mainly discuss the mechanism underlying the apoptosis of DCs upon septic
insults. It was observed in both human and murine sepsis models that caspase-3-me-
diated apoptosis of DCs led to the loss of DCs, resulting in immunosuppressive status
and increased mortality [68, 73]. By employing a caspase-3 inhibitor or generating Cas-
pase-3−/− mice, along with the upregulation of the anti-apoptotic protein B-cell lym-
phoma-2 (Bcl-2) in DCs mice (referred to as DCs-hBcl-2 mice), the survival of DCs was
enhanced, the immunosuppression induced by lipopolysaccharide (LPS) was attenuated,
and the resistance to lethal endotoxic shock was increased. Consequently, this led to
Page 8 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
an improvement in the unfavorable consequences of sepsis [66, 67, 74]. Further studies
showed that pro-apoptotic and anti-apoptotic proteins were closely associated with the
occurrence of apoptosis of DCs in sepsis. For example, mice with Bim knockout signifi-
cantly decreased apoptosis of DCs during sepsis induction [75]. Other reports have indi-
cated that sepsis-induced apoptosis of DCs accompanied with ceramide generation by
activating acid sphingomyelinase (A-SMase). LPS and TNF-α induced proinflammatory
response and apoptosis of DCs in mice were substantially mitigated by being treated
with the A-SMase inhibitor including imipramine. Notably, A-SMase involvement in
apoptosis was more common in immature DCs as immature DCs were more sensitive to
ASMase-induced apoptosis. In a sepsis mouse model, the activation of cGMP-depend-
ent protein kinases (PKG) by nitric oxide (NO) counteracted the apoptosis of immature
DCs induced by A-SMase. In septic mice, the apoptosis of immature DCs was signifi-
cantly increased when inducible nitric oxide synthase (iNOS−/−) was knocked out [76].
In addition, apoptosis of splenic DCs can be activated through TLR4 and TLR2 sign-
aling pathways, followed by activating interferon regulatory factor 1 (IRF1) through a
TLR4-dependent, myeloid differentiation primary response gene 88 (MyD88)-independ-
ent manner [59, 77]. Moreover, it has been documented that a pathway independent
of TLR4 engagement can trigger LPS-induced apoptosis of DCs via CD14 and activate
calcineurin-activated T nuclear factor (NFAT) [78]. So far, the mechanism concerning
sepsis-induced apoptosis of DCs has not been fully elucidated. Further study of its spe-
cific mechanism will provide a new therapeutic strategy for managing sepsis-induced
immunosuppression related to apoptosis of DCs (Fig.2).
Necroptosis
Necroptosis is mainly mediated by TNFR and TLR family members, IFN, intracellular
RNA, and DNA sensors. Afterward, receptor proteins are interacted with by protein
kinases such as receptor-interacting protein kinase (RIPK)1 and RIPK3, which trans-
mit death signals and phosphorylate mixed-lineage kinase domain-like protein (MLKL).
MLKL acts as an initiator of cell death and eventually induces necroptosis [79]. e pro-
cess of necroptosis leads to the liberation of various molecular patterns associated with
damage (DAMPs), such as mitochondrial DNA (mtDNA), high mobility group box-1
protein (HMGB1), and lactate dehydrogenase (LDH). ese substances further enhance
and intensify the inflammatory cascade, significantly worsening the clinical outcomes of
sepsis patients [80, 81].
Emerging evidence has suggested that the RIPK1–RIPK3–MLKL-mediated necrop-
tosis and the release of large amounts of DAMPs can increase mortality in TNF-
α-induced sepsis. Ripk3−/− showed a marked protective effect on mice after CLP
operation, thus significantly reducing the mortality of septic animals [82–84]. Addi-
tional research has indicated that necroptosis takes place concurrently in the liver,
intestines, and lungs during sepsis, thereby playing a role in the emergence of multi-
ple organ dysfunction syndrome (MODS) in sepsis [85–87]. In addition, the markers
of necroptosis RIPK1, RIRK3, and MLKL and the HMGB1 released by necroptosis
in peripheral blood of septic patients were significantly increased and positively cor-
related with the severity and mortality attributed to sepsis [88, 89]. Using necroptosis
inhibitors such as Nec-1, GSK2982772, and ZB-R-55 could alleviate sepsis-induced
Page 9 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
acute liver and lung injury, release inflammatory mediators in serum, and reduce
mortality in septic mice [90–94]. Further data revealed that downregulation of
RIPK3 expression reduced necroptosis, which might be related to its ability to affect
the transcription of activating transcription factor 6 (ATF6) and mitigate excessive
ERS [92]. Research conducted on monocyte-derived dendritic cells (MDDCs) in the
peripheral blood of individuals with septic shock revealed that MDDCs in patients
who survived primarily experienced apoptosis through a caspase-dependent pathway,
whereas MDDCs in patients who did not survive were exposed to the necroptotic
pathway. Circulating histones are identified as critical mediators of DC necrotiz-
ing cell death, which could be rescued by recombinant human-activated protein C
(rh-APC) [95]. Notably, other studies showed that the treatment with Nec-1 could
not improve the survival of septic mice [96]. is paradoxical phenomenon may be
Fig. 2 Apoptosis of dendritic cells (DCs) in sepsis. The apoptosis of DCs in sepsis mainly includes intrinsic
or mitochondrial pathway and extrinsic or death receptor signaling. There is extensive crosstalk between
these two apoptotic pathways; the extrinsic pathway triggers the intrinsic pathway by activating caspase‑8
to produce truncated bid (tBid), and the intrinsic pathway can amplify the extrinsic pathway by activating
caspase‑3/‑7 with activated caspase‑9. The interaction of these two pathways eventually leads to typical
apoptotic features, such as DNA fragmentation, chromatin condensation, cell shrinkage, and membrane
blistering. Nonclassical apoptosis of DCs in sepsis is accompanied by the generation of ceramide through
the activation of A‑SMase. This pathway can be antagonized by NO and A‑SMase inhibitors including
imipramine. TLR, Toll‑like receptor; TNFR, TNF receptor; FADD, Fas‑associated with death domain protein;
RIP, receptor‑interacting protein; TRAF2, TNF receptor associated factor 2; TRADD, TNFRSF1A‑associated via
death domain; TRIF, Toll/interleukin‑1 receptor domain containing adaptor inducing IFN‑β; APAF‑1, apoptotic
protease activating factor‑1; MOMP, mitochondrial membrane potential; A‑SMase, acid sphingomyelinase;
PKG, cGMP‑dependent protein kinases; iNOS, inducible nitric oxide synthase
Page 10 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
attributed to differences in the dosages of Nec-1 and animal models [97, 98]. ese
contradictory results are not fully explained. Nevertheless, both of them confirmed
that RIPK1 kinase activity is essential for the survival of animals subjected to sepsis
[99]. As knockout Ripk1 could result in death in mice, O’Donnell etal. constructed
Ripk1 DC KO mice, and the experiments demonstrated that necroptosis of DCs might
underlie the hyperinflammatory syndrome and immunosuppression in severe sepsis
[100]. It is important to conduct additional research to elucidate the exact regulatory
pathway of necroptosis in DCs during sepsis (Fig.3).
Fig. 3 Necroptosis of dendritic cells (DCs) in sepsis. Activation of multiple cellular receptors can trigger
necroptosis. These include death receptors (e.g., Fas), TLR, and TNFR. After the receptor is activated, it binds
to the adaptor protein, resulting in the downstream recruitment of RIPK1, which is deubiquitinated and
then phosphorylated, followed by phosphorylation of RIPK3 by p‑RIPK1 and phosphorylation of MLKL by
p‑RIPK3. Taken together, the phosphorylated forms of these three form necrosomes, which punch holes
in the cell membrane and subsequently lead to cell rupture and leakage of cell contents. In addition,
histones can induce necroptosis, and rh‑APC can rescue it. Also, ERS‑related proteins are involved in the
occurrence of necroptosis, but the detailed mechanism is still unrevealed. TLR, Toll‑like receptor; TNFR,
TNF receptor; FADD, Fas‑associated with death domain protein; TRAF2, TNF receptor associated factor 2;
TRADD, TNFRSF1A‑associated via death domain; TRIF, Toll/interleukin‑1 receptor domain containing adaptor
inducing IFN‑β; RIPK, receptor‑interacting protein kinase; MLKL, mixed‑lineage kinase domain‑like protein;
PERK, PKR‑like endoplasmic reticulum kinase; ATF6, activating transcription factor 6; IRE1α, inositol‑requiring
enzyme 1α; rh‑APC, recombinant human‑activated protein C
Page 11 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
Pyroptosis
Pyroptosis represents an RCD commonly initiated by inflammasomes, characterized
by cell swelling, membrane blebbing, DNA fragmentation, and eventually cell lysis. e
occurrence of pyroptosis relies on the inflammatory caspase and the Gasdermin protein
family. e classical pyroptosis pathway is often described as occurring through a two-
step process. NF-κB is activated to induce the expression of various proteins, assembling
a complex called the inflammasome in the “activating signal” step. Typically, inflammas-
omes are composed of a cytosolic pattern recognition receptor [PRR; for example, mem-
bers of the NOD-like receptor (NLR) family, NLRP1, NLRP3, and NLRC4], an adaptor
protein containing the CARD domain (such as ASC), and pro-caspase-1. Of note, one
well-accepted approach to monitor pyroptotic activity is to analyze inflammasome
activation by detecting NLRP3 and visualizing ASC specks. Regarding the subsequent
phase of activation, following the cleavage of Gasdermin D (GSDMD) by caspase-1, the
N-terminal portion of GSDMD assembles into clusters and generates pores in the cell
membrane, ultimately resulting in cell disruption and the liberation of cytokines. Con-
comitantly, pro-IL-1β and pro-IL-18 are activated by proteolysis to generate their active
forms, which are secreted from the cell via the pores. erefore, pyroptosis serves as
a vital natural defense mechanism and significantly contributes to the body’s ability to
fend off harmful pathogens [101].
In recent decades, a growing number of studies have investigated pyroptosis and
its relationship with sepsis [102–104]. Previously, pyroptosis was thought to occur
only in monocytes or macrophages, while subsequent results indicated that it could
also occur in other cell types [105]. Moderate pyroptosis is beneficial for the body to
clear the pathogens, while excessive pyroptosis will lead to host immune dysfunction,
multi-organ dysfunction, and even death [106–108]. In sepsis, the occurrence of mac-
rophage pyroptosis was observed, and the survival rate of septic mice was enhanced
by inhibiting the inflammatory response of macrophages through NLRP3 knockout,
leading to an improvement [109]. It is likely that different ways to reduce lipid peroxi-
dation markedly reduced the mortality of septic mice by decreasing pyroptosis of mac-
rophages [110]. However, whether or not pyroptosis of DCs occurs in sepsis remains
controversial. Erlich etal. noted that only monocytes and macrophages were involved
in pyroptosis [111]. Guermonprez etal. reported that DCs had a class of iDCs mani-
fested as M-CSFR+CD209a+ that could develop into pyroptosis [112]. In recent years,
our team confirmed that pyroptosis of CD11c+CD11bintMHC-IIhiCD135+CD115− DC
cells increased significantly in the state of sepsis [113]. Mechanistically, it has been
implicated that ERS can activate NLRP3 inflammasome [114, 115]. Our data confirmed
that ERS was overactivated during sepsis, which facilitated ERS-associated NLRP3 acti-
vation. Furthermore, the study discovered that Sestrin2 (SESN2) effectively suppressed
excessive activation of the NLRP3 inflammasome and the resulting caspase-1-dependent
pyroptosis, leading to an enhanced prognosis in sepsis. is was achieved by stabilizing
the endoplasmic reticulum (ER), highlighting the importance of identifying novel thera-
peutic targets for sepsis treatment [113].
In the pathogenesis of sepsis, DCs also exhibit harmful effects on organisms through
the nonclassical pathway, known as caspase11-dependent pyroptosis. Zanoni etal. found
that LPS stimulation induced caspase-11-dependent pyroptosis of DCs with IL-1 release
Page 12 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
[116]. Kumari etal. further demonstrated the harmful impact of caspase-11 on CD11c+
cells in LPS-induced septic shock [117] (Fig.4).
Ferroptosis
Ferroptosis, a distinct form of cell death introduced in 2012, is induced by the oxida-
tion of phospholipids dependent on iron [105]. Although no chromatin condensation or
loss of plasma membrane integrity is found in the morphological characteristics, mito-
chondrial concentration, reduction in mitochondrial cristae, and increase of membrane
density can be observed. Different cellular metabolic pathways, such as redox homeosta-
sis, iron metabolism, mitochondrial function, and the metabolism of amino acids, lipids,
and sugars, along with various disease-related signaling pathways, regulate ferroptosis
[118]. Ferroptosis can be induced by various substances, including erastin and RSL3
as experimental reagents, sorafenib, sulfasalazine, statins, and artemisinin as approved
drugs, ionizing radiation, and cytokines such as IFN-γ and TGF-β1 [119]. e regulatory
Fig. 4 Pyroptosis of dendritic cells (DCs) in sepsis. Pyroptosis of DCs is mainly recognized by TLRs, then
activates inflammasomes, including NLRP3 and other inflammasomes. Pro‑caspase‑1 in inflammasomes
activates the active form caspase‑1, which cleaves Gasdermin family proteins such as GSDMD. Its N‑terminal
oligomerizes and punches pores on the cell membrane, resulting in cell membrane rupture. In addition,
caspase‑1 cleaves IL‑1β and IL‑18 precursors, so they become active and are secreted outside the cell through
pores. Recent studies have demonstrated that excessive ERS in sepsis will lead to inflammasome activation
and promote pyroptosis of DCs. Sestrin2 can alleviate the above harmful process, inhibit sepsis‑induced
pyroptosis of DCs, and reduce the mortality of septic mice. LPS, lipopolysaccharide; TLR, Toll‑like receptor;
PERK, PKR‑like endoplasmic reticulum kinase; ATF4, activating transcription factor 4; eIF2α, eukaryotic
initiating factor 2α; CHOP, C/EBP homologous protein; NLRP3, nucleotide binding oligomerization domain
(NOD)‑like receptor protein 3; ASC, apoptosis speck‑like protein containing a caspase recruitment domain;
GSDMD, Gasdermin D; IL, interleukin; TNF, tumor necrosis factor; HMGB1, high mobility group box‑1 protein
Page 13 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
process of ferroptosis involves both the conventional pathway mediated by glutathione
peroxidase 4 (GPX4) and the alternative pathway that is independent of GPX4 [120].
Cystine is transported into the cell through the reverse transporter of cystine/glutamate
(system Xc−) in the canonical controlling pathway of GPX4. Subsequently, it undergoes
reduction to cysteine in a manner that depends on glutathione (GSH) and/or thiore-
doxin reductase 1 (TXNRD1). ese processes promote the biosynthesis of GSH. GSH
functions as a powerful suppressor that enhances the intracellular conversion of phos-
pholipid hydroperoxides (PLOOHs) to PLOOHs-corresponding alcohols (PLOHs) by
acting as a coenzyme of GPX4. PLOOHs, known as lipid-derived reactive oxygen species
(ROS), are believed to function as the primary agents responsible for executing ferropto-
sis. e most extensively researched noncanonical regulatory pathways of ferroptosis are
the ferroptosis suppressor protein 1 (FSP1)/ubiquinone (CoQ10) system and the GTP
cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4) system [118]. Remarkably, ferritin
degradation (referred to as ferritinophagy), a burgeoning area of interest in ferroptosis
investigation, is responsible for the elevation of Fe2+ levels within cells. e aggregation
of Fe2+ produces hydroxyl radicals (·OH) through the Fenton reaction and induces lipid
peroxidation and ferroptosis [119].
Increasing evidence has been suggested that ferroptosis appears to be vital in the devel-
opment of sepsis [103, 121, 122]. Many reports in animal models of sepsis have indicated
that ferroptosis is increased and closely related to sepsis-induced cardiac, liver, and lung
injury secondary to LPS-induced endotoxemia and CLP surgery [123–126]. Ferroptosis
inhibitors such as ferrostatin-1 (Fer-1), sevoflurane (Sev), panaxydol (PX), and irisin can
abate sepsis-induced multiple organ dysfunction and improve survival rates [124–129].
Clinical trials demonstrated a reduction in serum irisin levels among septic individu-
als, which exhibited a negative correlation with the acute physiology and chronic health
evaluation (APACHE) II score. Treatment with irisin may offer therapeutic potential
in managing sepsis [126]. Similarly, changes in the regulation of iron levels in the body
were noted in individuals with sepsis, and increased levels of iron in the blood and fer-
ritin were found to have a positive association with the sequential organ failure assess-
ment (SOFA) score and patient mortality in sepsis cases [130]. In our study, we noticed
that DCs in a septic state presented with ferroptosis, which could significantly hinder
DC maturation. To this end, the administration of Fer-1 could relieve such impact. Fur-
ther research demonstrated that SESN2 protected DCs against sepsis-induced ferrop-
tosis through an activating transcription factor 4 (ATF4)–C/EBP homologous protein
(CHOP)–cation transport regulator homolog 1 (CHAC1)-dependent manner [50, 131]
(Fig.5).
Autophagy‑dependent cell death
ADCD is a type of RCD that relies on the autophagic machinery (or its components)
mechanistically [132]. The traditional comprehension of ADCD is a death due to
excessive self-consumption of organelles and cytoplasmic content that depends on
autophagy genes and requires autophagy flux [133, 134]. Recently, this has been
questioned due to the identification of autosis as a form of ADCD, which is a death
due to activation of the Na+/K+-ATPase pump, changes in membrane osmolarity,
and ion transport, which is dependent on autophagy genes but not autophagy flux
Page 14 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
[135, 136]. Currently, there are three ADCD types: excessive autophagy, excessive
organelle-specific autophagy, and autosis [137, 138]. Autophagy can protect cells or
trigger cell death [9, 139]. Autophagy was shown to be involved in DC functions at
several levels [57, 140, 141]. A loss of autophagy in DCs caused a sepsis-like condi-
tion, including tissue inflammation and hyperproduction of inflammasome-related
cytokines [142]. Impaired PINK1/Parkin-mediated mitophagy renders apoptosis of
DCs, resulting in sepsis-induced immunosuppression [143]. Due to the extensive
intersection of autophagy with apoptotic and necrotic signals and the complexity of
the association between ADCD and apoptosis, necrosis, and ferroptosis, the defini-
tion of ADCD has been controversial [144–148]. Exploring the precise regulation
of “lethal” and “nonlethal” autophagy flux in DCs during sepsis may provide a new
therapeutic approach for sepsis [149] (Fig.6).
Fig. 5 Ferroptosis of dendritic cells (DCs) in sepsis. The primary mechanism of ferroptosis is the accumulation
of ferrous iron in the intracellular and the initiation of lipid peroxidation through the Fenton reaction. GPX4
is the only glutathione peroxidase (GPX) used for lipid peroxide reduction in cells. Inactivation of GPX4 will
contribute to lipid peroxidation and then induce ferroptosis. Many studies have indicated that DCs in a septic
state have obvious ferroptosis. Sestrin2 can protect DCs against sepsis‑induced ferroptosis through the ATF4–
CHOP–CHAC1 signaling pathway. GPX4, glutathione peroxidase 4; GSH, glutathione; PLOOH, phospholipid
hydroperoxide; PLOH, PLOOHs‑corresponding alcohol; ROS, reactive oxygen species; ATF4, activating
transcription factor 4; CHOP, C/EBP homologous protein; CHAC1, cation transport regulator homolog 1
Page 15 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
Targeting DCs duringsepsis
Since sepsis-induced immunosuppression mediated by DC dysfunction is crucial for the
prognosis of septic patients. In the past decades, there have been a number of immune-
modulatory therapies that could impact DC function and survival, although they are
not DC specific, including anti-PD-1, anti-PDL1, anti-FAS, anti-CTLA4, etc. [5, 8, 26,
150, 151]. Some of the clinical trials related to it are still ongoing. (ClinicalTrials.gov
ID NCT01161745 and ClinicalTrials.gov ID NCT05126537). Targeting DC dissonance
brings about the possibility of the effective treatment of sepsis. Current measurements
of DCs can be mainly divided into two categories: modifying immune functions of DCs
and inhibiting cell death of DCs (Table1).
Modifying immune functions ofDCs
e cytokine IL-12 facilitates the release of inflammatory substances, leading to the
secretion of IFN-γ and causing lethality in septic shock induced by LPS [152]. Glu-
cocorticoids (GCs) are vital regulatory compounds in the body that have a significant
impact on the body’s development, growth, metabolism, and immune function. ey
also have potent anti-inflammatory and immunosuppressive properties [153–155]. It
Fig. 6 Autophagy‑dependent cell death (ADCD) of dendritic cells (DCs) in sepsis. Autophagy refers to the
process of autophagosome formation, isolation of cytosol and organelles, and transport to lysosomes for
degradation and recycling of macromolecules. However, when autophagy is overactivated, it can lead to
ADCD. mTORC1, mammalian target of rapamycin C1; ULK1, unc‑51‑like kinase 1; PI3K, phosphoinositide 3
kinase; PINK1, PTEN‑induced putative kinase 1; LC3B, microtubule‑associated protein 1 light chain 3 β
Page 16 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
has been shown that endogenous GCs inhibit the response of DCs to LPS exposure,
reduce the production of IL-12, and augment the loss of CD8+ DCs, thereby play-
ing a lifeguard role in the high-inflammatory phase of sepsis [152, 156]. According
to the present guidelines for sepsis treatment, it is advised to administer intravenous
corticosteroids to adult patients experiencing septic shock and requiring continuous
vasopressor support [157]. In individuals suffering from severe sepsis but not experi-
encing septic shock, the administration of hydrocortisone did not result in a decrease
in the likelihood of developing septic shock within a 14-day period when compared
with the use of placebo controls (ClinicalTrials.gov ID NCT00670254) [158]. Never-
theless, the precise dosage, initiation timing, and duration of corticosteroids are still
unclear. e hydrocortisone-plus fludrocortisone group had a lower mortality rate
Table 1 Immunotherapy targeting DCs in sepsis
DCs, dendritic cells; IL, interleukin; IFN, interferon; TNF, tumor necrosis factor; Treg, regulatory T cells; TLR, Toll-like receptor;
HMGB1, high mobility group box-1 protein; PLA2, phospholipase A2; miRNAs, microRNAs; VIM, vimentin
Strategies Treatment Major functions References
Modifying functions of DCs Glucocorticoids Reducing the production of
IL‑12 and augmenting the loss of
CD8+ DCs
[152–160]
Thymosin α1 Enhancing the expression of DCs
surface molecules; upregulating
the expression of TLR2 and TLR9
on the surface of DCs; promoting
the secretion of IL‑2, IL‑12, and
IFN‑α
[161–165]
TLR4 antagonist FP7 and Eritoran Inhibiting cytokines storm and
glycolysis reprogramming of DCs [59, 166–171]
TLR2‑derived peptides Upregulating CD14 activity and
promoting antigen‑mediated
DCs maturation; increasing the
release of IL‑12 and IFN‑γ and
decreasing the release of TNF‑β;
promoting the differentiation of
T cells toward Th1
[172, 173]
PLA2 Increasing the expression of
surface molecules of DCs and
promoting DC maturation
[174, 175]
Anti‑HMGB1 antibody Augmenting maturation of DCs
and T cell polarization toward
Th1
[176–180]
Anti‑C5a antibody Enhancing IL‑12+ DCs in the
abdominal cavity and inhibiting
them in peripheral blood and
lymph nodes
[181–191]
Inhibiting cell death of DCs Silencing of miR‑142‑p, miR155,
and miR‑146a/b Inhibiting the apoptosis of DCs;
increasing production of proin‑
flammatory cytokines such as
IL‑12p70, IL‑6, TNF‑α, and IFN‑γ
[192–194]
Overexpressed VIM Inhibiting apoptosis of DCs
Inhibiting production of proin‑
flammatory cytokines such as
IL‑2, IL‑10, and IFN‑α
[195]
Dexmedetomidine Inhibiting the apoptosis of DCs;
downregulating the production
of sepsis‑induced inflammatory
mediators, including TNF‑α and
IL‑6
[196–198]
Page 17 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
compared with the placebo group in clinical trials involving adults with septic shock
(ClinicalTrials.gov ID NCT00625209) [159]. Clinical trials of the effects of early use
of dexamethasone in patients with high-risk sepsis are ongoing (ClinicalTrials.gov ID
NCT05136560) [160]. e safety and efficacy of glucocorticoids in treating sepsis and
the concrete signaling pathways need to be further clarified.
ymosin α1 is a small-molecule polypeptide purified from the calf thymus with
a nonspecific immune effect. Its chemical and spatial structure are apparent; its main
active ingredient consists of 28 amino acids. Research has indicated that the adminis-
tration of thymosin α1 can improve the capacity of T cells to generate and release IFN-
γ, as well as increase the HLA-DR expression in monocytes [161]. Likewise, it has the
potential to enhance the presentation of surface markers on DCs, such as CD40, CD80,
MHC-I, and MHC-II, thereby stimulating the differentiation and activation of DCs
[162]. Furthermore, thymosin α1 has the ability to increase the levels of TLR2 and TLR9
on the outer layer of DCs [163], as well as enhance the release of inflammatory cytokines
such as IL-2, IL-12, and IFN-α [164]. Preclinical studies have documented that it can
help restore immune response and improve the survival of patients with sepsis [165].
Clinical trials on the long-term prognosis of immunotherapy with thymosin α1 in sep-
tic patients are ongoing (ClinicalTrials.gov ID NCT04901104). Studying the regulation
of the TLRs signaling pathway is significant because of abnormal TLR involvement in
sepsis pathogenesis. It has been established that TLR2 and TLR4 are critically involved
in the sepsis-induced depletion of splenic DCs [59, 166, 167]. Further studies showed
that the TLR4 antagonist FP7 inhibited LPS-induced cytokine production and DC gly-
colysis reprogramming, and protected mice from fatal viral sepsis, most likely by reduc-
ing the TLR4-dependent cytokine storm mediated by DAMPs such as HMGB1 [168].
Positive results were observed in both phase I and II trials investigating the impact of
the MD2-TLR4 antagonist Eritoran on poor outcomes in patients with severe sepsis.
However, phase III trials demonstrated that Eritoran did not decrease the 28-day mor-
tality in patients with severe sepsis when compared with placebo controls (ClinicalTri-
als.gov ID NCT00334828) [169]. CD14, as a co-receptor of TLR7 and TLR9, plays a role
in recognizing the common signals of pathogen-associated molecular patterns (PAMPs)
and can be a potential target for regulating DC-mediated 1 differentiation [170, 171].
TLR2-derived peptides can augment CD14 activity and promote antigen-induced DC
maturation by upregulating MHC-II, CD80, and CD86 expressions. In this regard, the
peptide increases the release of IL-12 and IFN-γ from DCs, inhibits the formation of
TNF-β, promotes the differentiation of T cells toward 1, and improves the immuno-
suppressive state [172]. Other studies have implicated that immunosuppression induced
by sepsis is related to serum TLR-9 level [173]. Taken together, targeting TLRs may be
an exciting and promising area of sepsis therapy.
Phospholipase A2 (PLA2) is an enzyme that facilitates the hydrolysis of the 2-acyl
moiety on glycerol molecules of phospholipids. In septic patients, there is a notable
increase in the serum levels of PLA2, particularly the secretory PLA2-IIA (sPLA2-IIA),
which can serve as a dependable indicator for diagnosing sepsis (ClinicalTrials.gov ID
NCT03953404) [174]. sPLA2 can enhance the expression of CD86, CD80, CD83, and
CD40 on the surface of DCs, promote DC maturation, and improve the prognosis of
sepsis (ClinicalTrials.gov ID NCT00034476) [175].
Page 18 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
HMGB1 is a potent proinflammatory cytokine at the late stage of sepsis and is associ-
ated with delayed death from endotoxin and sepsis [176]. HMGB1 plays a dual role in
regulating the immune functions of DCs. It activates DC maturation and T-cell polar-
ization toward 1 at a specific concentration and stimulation time. Nevertheless, an
overabundance of HMGB1 stimulation can result in atypical development and impaired
immune function of DCs [177]. Anti-HMGB1 antibody treatment and specific inhibition
of DC secretion of HMGB1 by small interfering RNA (siRNA) of HMGB1 significantly
reduce sepsis-induced mortality, which may provide a treatment strategy for sepsis [178,
179]. HMGB1 is a marker of cell damage and activation and is known to increase in ICU
patients. It was found in clinical trials that HMGB1 levels elevated in study participants
hospitalized 3–6months after ICU admission, although there was no association with
the primary outcome, physical performance (ClinicalTrials.gov ID NCT02914756) [180].
Another clinical study with regard to the pro-inflammatory effects of blood platelets
(including plasma concentration in HMGB1) in critically ill patients with septic shock is
ongoing (ClinicalTrials.gov ID NCT04080453).
Basically, C5a is a necessary complement and a powerful chemokine overactivated
during sepsis [181, 182]. It modulates the balance of cytokines and DC distribution by
regulating the expression of adherent cytokines [183–186]. C5a promotes the movement
of IL-12+ DCs from the peritoneal cavity to both lymph nodes and peripheral blood.
Additional research indicates that IL-12+ DCs facilitate the proliferation of pathogenic
IL-17+ T helper cells (17) and IFN-γ+ T helper cells (1) [181, 187, 188]. Moreover,
excessive expression of IL-12+ DCs detrimentally affects the host during a septic condi-
tion [189, 190]. In septic mice treated with anti-C5a antibody, IL-12+ DCs in peripheral
blood and lymph nodes decreased, while IL-12+ DCs in the abdominal cavity increased
and exerted a protective impact, thereby improving the prognosis of mice subjected
to septic challenge [181]. In a clinical study, a new extracorporeal treatment for sepsis
showed promising results. By using immunoadsorption (IA) therapy, the levels of cir-
culating endotoxin, IL-6, and C5a were significantly reduced, leading to the reversal of
antigen-presenting cell deactivation and improvement in organ functions (ClinicalTrials.
gov ID NCT00146432) [191].
Inhibiting cell death ofDCs
Currently, the apoptosis of DCs represents the most extensively studied attempt to
restore the number of DCs.
MicroRNAs (miRNAs) are a type of RNA that is not involved in coding and is pro-
duced by genes within the organism. ey are approximately 22 nucleotides long and
play a role in controlling gene expression after transcription. Many studies have demon-
strated that a variety of miRNAs are induced to express during the development, matu-
ration, and differentiation of monocytes into DCs, including miR-142-p, miR-155, and
miR-146a/b, which will lead to increased apoptosis of DCs and change the function of
DC-mediated cytokines. Inhibiting these genes greatly reduces the apoptosis of DCs and
enhances the synthesis of proinflammatory cytokines such as IL-12p70, IL-6, TNF-α,
and IFN-γ, thereby substantially enhancing the survival rates in response to endotoxin-
induced conditions [192–194]. Studies have been carried out to investigate the possible
function of miRNAs (miR-223, miR-15a, miR-16) in controlling the growth and death
Page 19 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
of lymphocytes during sepsis (ClinicalTrials.gov ID NCT02756559). ese findings on
miRNAs suggest that miRNAs can be used as a new strategy for treating sepsis.
e findings of the clinical trial indicated that individuals diagnosed with sepsis and
septic shock exhibited notably elevated serum vimentin (VIM) levels in comparison
with the control group. In cell experiments, it was observed that the upregulation of cas-
pase-3 expression was significant in VIM-deficient cells when compared with control
cells. In contrast, caspase-3 was reduced by nearly 40% in cells that overexpressed VIM.
IL-2, IL-10, and IFN-α levels were significantly lower in VIM-deficient cells than those
in control cells, while there was no significant change in cells with high VIM expression.
ese findings indicate that VIM regulates apoptosis and inflammatory response of lym-
phocytes. e identification and prediction of patients’ outcomes with sepsis or septic
shock could potentially benefit from focusing on VIM as a new approach [195] (Clinical-
Trials.gov ID NCT03253146).
Multiple clinical trials have demonstrated that sedation strategies using dexmedetomi-
dine mitigate excessive inflammation, improve renal function, shorten the time required
for mechanical ventilation, and reduce mortality in patients with sepsis. e potential
causes could be associated with dexmedetomidine in reducing the generation of sepsis-
triggered inflammatory substances, such as TNF-α and IL-6, and preventing apoptosis
[196–198] (ClinicalTrials.gov ID NCT01760967).
Future perspectives andremarks
Septic shock and the consequent MODS, which are leading causes of death in critically
ill patients, often arise as a result of sepsis, a frequent complication in individuals with
trauma/burns, infection, and severe internal/surgical conditions. e immune response
of the host during sepsis encompasses intricate pathophysiological mechanisms. e
exact molecular mechanism and key regulatory pathways of immune dysfunction in sep-
sis remain to be elucidated [7, 9, 10, 199]. In clinical practice, it is imperative to monitor
and control the immune function of patients suffering from sepsis [200]. Understand-
ing how immune cells change in function and number in sepsis can aid in elucidating
its pathophysiology and improving prognosis. DCs are known to be the most powerful
APCs in the body and essential regulatory cells of the immune system, and they can be
roughly divided into three subgroups: cDCs, pDCs, and FDCs. In the pathogenesis of
sepsis, the functions and quantity of DCs undergo significant changes; the main symp-
tom is an impairment of DCs and a substantial decrease in their amount. e dissonance
of DCs is characterized by abnormal surface molecular expression, cytokine secretion,
and dampened T cell-stimulatory capacity. Marked reduction in the number of DCs dur-
ing sepsis involves various pathways, with apoptosis being the most extensively investi-
gated. Lately, there has been a growing interest in research concerning recently identified
RCD, which encompasses necroptosis, pyroptosis, ferroptosis, and ADCD. Modulating
the RCD of DCs in sepsis would be a new treatment target. Targeting DCs to regulate
host immunity has become a crucial research field in sepsis due to their critical role in
the immune response. In recent times, numerous approaches have been formulated and
effectively employed to mitigate atypical immune reactions during the advancement of
sepsis, encompassing the alteration of DCs’ functionalities and the suppression of DCs’
Page 20 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
cell death. Although these treatments are still in preclinical trials and have not proven
effective for septic patients, they hold immense potential for clinical management.
To conclude, further study is needed to understand the potential role of DCs in sepsis.
A thorough investigation into the molecular basis of DCs during sepsis and the develop-
ment of novel treatment strategies targeting DCs might improve immune-modulatory
processes against septic insults.
Abbreviations
ICU Intensive care unit
LMICs Low‑ and middle‑income countries
DCs Dendritic cells
APCs Antigen‑presenting cells
TCRs T cell surface receptors
MHC Major histocompatibility complex
HLA‑DR Human leukocyte antigen‑DR
MHC‑II MHC class II
IL Interleukin
scRNA‑seq Single‑cell RNA sequencing
CytoF Cytometry by time‑of‑flight
PCD Programmed cell death
ADCD Autophagy‑dependent cell death
cDCs Classical or conventional DCs
pDCs Plasmacytoid dendritic cells
FDCs Follicular dendritic cells
CMPs Common myeloid progenitors
LCs Langerhans cells
TLRs Toll‑like receptors
CLPs Common lymphoid progenitor
IFN Interferon
CXCL CXC chemokine ligand
NF‑κB Nuclear factor κ‑B
MPCs Mesenchymal progenitor cells
mregDCs Mature DCs enriched in immunoregulatory molecules
CLP Cecal ligation and puncture
BALF Bronchoalveolar lavage fluid
TNF Tumor necrosis factor
TGF Transforming growth factor
Tregs Regulatory T cells
HSPCs Hematopoietic stem cells and hematopoietic progenitor cells
ERS Endoplasmic reticulum stress
TNFAIP8L2 Tumor necrosis factor α‑induced protein 8 like‑1
PD‑L1 Programmed cell death‑ligand 1
PD‑1 Programmed death 1
TAK1 TGF‑β‑activated kinase 1
JNK C‑Jun N‑terminal kinases
PTEN Protein tyrosine phosphatase
PINK1 PTEN‑induced putative kinase 1
NCCD Nomenclature Committee on Cell Death
ACD Accidental cell death
RCD Regulated cell death
APAF‑1 Apoptotic protease activating factor‑1
TNFR TNF receptor
Fas Factor associated suicide
TRAIL TNF‑related apoptosis‑inducing ligand
TRAILR TRAIL receptor
Bcl‑2 B‑cell lymphoma‑2
PI3K Phosphoinositide 3 kinase
LPS Lipopolysaccharide
A‑SMase Acid sphingomyelinase
PKG CGMP‑dependent protein kinases
iNOS Inducible nitric oxide synthase
IRF Interferon regulatory factor
MyD88 Myeloid differentiation primary response gene 88
NFAT Calcineurin‑activated T nuclear factor
RIPK Receptor‑interacting protein kinase
MLKL Mixed‑lineage kinase domain‑like protein
Page 21 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
DAMPs Damage ‑related molecular patterns
mtDNA Mitochondrial DNA
HMGB1 High mobility group box‑1 protein
LDH Lactate dehydrogenase
MODS Multiple organ dysfunction syndrome
ATF6 Activating transcription factor 6
MDDCs Monocyte‑derived DCs
rh‑APC Recombinant human‑activated protein C
PRR Pattern recognition receptor
NLR NOD‑like receptor
GSDMD Gasdermin D
SESN2 Sestrin2
GPX4 Glutathione peroxidase 4
GSH Glutathione
TXNRD1 Thioredoxin reductase 1
PLOOHs Phospholipid hydroperoxides
PLOHs PLOOHs‑corresponding alcohols
ROS Reactive oxygen species
FSP1 Ferroptosis suppressor protein 1
CoQ10 Ubiquinone
GCH1 GTP cyclohydrolase 1
BH4 Tetrahydrobiopterin
Fer‑1 Ferrostatin‑1
Sev Sevoflurane
PX Panaxydol
APACHE Acute physiology and chronic health evaluation
SOFA Sequential organ failure assessment
ATF4 Activating transcription factor 4
CHOP C/EBP homologous protein
CHAC1 Cation transport regulator homolog 1
GCs Glucocorticoids
PAMPs Pathogen‑associated molecular patterns
PLA2 Phospholipase A2
sPLA2‑IIA Group IIA secretory PLA2
siRNA Small interfering RNA
Th T helper cells
miRNAs microRNAs
VIM Vimentin
IA Immunoadsorption
Acknowledgements
The authors would like to thank all colleagues whose important publications were cited in this paper.
Author contributions
Y.M.Y. conceived the idea of this review. L.Y.Z. performed literature searching and wrote this paper. R.Q.Y. and X.H.D.
conducted language editing and rechecking literature. Y.D. and P.Y.H. checked and edited the content and format of this
manuscript before submission. M.Y.W. and S.T.W. undertook the drawing of tables and figures. All authors contributed to
the article and approved the submitted version.
Funding
This work was supported by grants from the National Key Research and Development Program (no. 2022YFA1104600),
the National Natural Science Foundation of China (nos. 82241062, 82130062), and the Beijing Natural Science Founda‑
tion (no. 7244296).
Availability of data and materials
Not applicable.
Declarations
Ethics approval and consent to participate
Not applicable. This review does not involve new data collection or experimental procedures on human participants or
animals.
Consent for publication
Not applicable. This review does not contain any individual person’s data in any form.
Competing interests
The authors have declared that no competing interest exists.
Received: 16 January 2024 Accepted: 21 May 2024
Page 22 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
References
1. Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic
shock (Sepsis‑3). JAMA. 2016;315(8):801–10.
2. Hotchkiss RS, Moldawer LL, Opal SM, Reinhart K, Turnbull IR, Vincent JL. Sepsis and septic shock. Nat Rev Dis Prim‑
ers. 2016;2:16045.
3. Cecconi M, Evans L, Levy M, Rhodes A. Sepsis and septic shock. Lancet. 2018;392(10141):75–87.
4. Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017:
analysis for the Global Burden of Disease Study. Lancet. 2020;395(10219):200–11.
5. Cavaillon JM, Singer M, Skirecki T. Sepsis therapies: learning from 30 years of failure of translational research to
propose new leads. EMBO Mol Med. 2020;12(4): e10128.
6. Rubio I, Osuchowski MF, Shankar‑Hari M, et al. Current gaps in sepsis immunology: new opportunities for transla‑
tional research. Lancet Infect Dis. 2019;19(12):e422–36.
7. van der Poll T, van de Veerdonk FL, Scicluna BP, Netea MG. The immunopathology of sepsis and potential thera‑
peutic targets. Nat Rev Immunol. 2017;17(7):407–20.
8. Delano MJ, Ward PA. The immune system’s role in sepsis progression, resolution, and long‑term outcome. Immu‑
nol Rev. 2016;274(1):330–53.
9. Venet F, Monneret G. Advances in the understanding and treatment of sepsis‑induced immunosuppression. Nat
Rev Nephrol. 2018;14(2):121–37.
10. Yao RQ, Ren C, Zheng LY, Xia ZF, Yao YM. Advances in immune monitoring approaches for sepsis‑induced immu‑
nosuppression. Front Immunol. 2022;13:891024.
11. Wu DD, Li T, Ji XY. Dendritic cells in sepsis: pathological alterations and therapeutic implications. J Immunol Res.
2017;2017:3591248.
12. Poehlmann H, Schefold JC, Zuckermann‑Becker H, Volk HD, Meisel C. Phenotype changes and impaired function
of dendritic cell subsets in patients with sepsis: a prospective observational analysis. Crit Care. 2009;13(4):R119.
13. Kumar V. Dendritic cells in sepsis: potential immunoregulatory cells with therapeutic potential. Mol Immunol.
2018;101:615–26.
14. Guilliams M, Ginhoux F, Jakubzick C, et al. Dendritic cells, monocytes and macrophages: a unified nomenclature
based on ontogeny. Nat Rev Immunol. 2014;14(8):571–8.
15. Villar J, Segura E. Decoding the heterogeneity of human dendritic cell subsets. Trends Immunol.
2020;41(12):1062–71.
16. Villani AC, Satija R, Reynolds G, et al. Single‑cell RNA‑seq reveals new types of human blood dendritic cells, mono‑
cytes, and progenitors. Science. 2017;356(6335): eaah4573.
17. See P, Dutertre CA, Chen J, et al. We are mapping the human DC lineage through the integration of high‑dimen‑
sional techniques. Science. 2017;356(6342): eaag3009.
18. Yao RQ, Li ZX, Wang LX, et al. Single‑cell transcriptome profiling of the immune space‑time landscape reveals
dendritic cell regulatory program in polymicrobial sepsis. Theranostics. 2022;12(10):4606–28.
19. Maier B, Leader AM, Chen ST, et al. Author correction: a conserved dendritic‑cell regulatory program limits antitu‑
mour immunity. Nature. 2020;582(7813):E17.
20. Grimaldi D, Louis S, Pène F, et al. Profound and persistent decrease of circulating dendritic cells is associated with
ICU‑acquired infection in patients with septic shock. Intensive Care Med. 2011;37(9):1438–46.
21. Roquilly A, McWilliam HEG, Jacqueline C, et al. Local modulation of antigen‑presenting cell development after
resolution of pneumonia induces long‑term susceptibility to secondary infections. Immunity. 2017;47(1):135‑147.
e5.
22. Guisset O, Dilhuydy MS, Thiébaut R, et al. Decrease in circulating dendritic cells predicts fatal outcome in septic
shock. Intensive Care Med. 2007;33(1):148–52.
23. Bouras M, Asehnoune K, Roquilly A. Contribution of dendritic cell responses to sepsis‑induced immunosuppres‑
sion and to susceptibility to secondary pneumonia. Front Immunol. 2018;9:2590.
24. Elsayh KI, Zahran AM, Lotfy Mohamad I, Aly SS. Dendritic cells in childhood sepsis. J Crit Care. 2013;28(5):881.e7‑13.
25. Weber GF, Maier SL, Zönnchen T, et al. Analysis of circulating plasmacytoid dendritic cells during the course of
sepsis. Surgery. 2015;158(1):248–54.
26. Vincent JL, Mongkolpun W. Non‑antibiotic therapies for sepsis: an update. Expert Rev Anti Infect Ther.
2019;17(3):169–75.
27. Sato K, Fujita S. Dendritic cells: nature and classification. Allergol Int. 2007;56(3):183–91.
28. Schraml BU, Reis e Sousa C. Defining dendritic cells. Curr Opin Immunol. 2015;32:13–20.
29. Macri C, Pang ES, Patton T, O’Keeffe M. Dendritic cell subsets. Semin Cell Dev Biol. 2018;84:11–21.
30. Anderson DA 3rd, Dutertre CA, Ginhoux F, Murphy KM. Genetic models of human and mouse dendritic cell devel‑
opment and function. Nat Rev Immunol. 2021;21(2):101–15.
31. Collin M, Bigley V. Human dendritic cell subsets: an update. Immunology. 2018;154(1):3–20.
32. O’Keeffe M, Mok WH, Radford KJ. Human dendritic cell subsets and function in health and disease. Cell Mol Life
Sci. 2015;72(22):4309–25.
33. Ueno H, Schmitt N, Klechevsky E, et al. Harnessing human dendritic cell subsets for medicine. Immunol Rev.
2010;234(1):199–212.
34. Darkwah S, Nago N, Appiah MG, et al. Differential roles of dendritic cells in expanding CD4 T cells in sepsis. Bio‑
medicines. 2019;7(3):52.
35. Collin M, McGovern N, Haniffa M. Human dendritic cell subsets. Immunology. 2013;140(1):22–30.
36. Haberman AM, Shlomchik MJ. Reassessing the function of immune‑complex retention by follicular dendritic cells.
Nat Rev Immunol. 2003;3(9):757–64.
37. Carroll MC, Isenman DE. Regulation of humoral immunity by complement. Immunity. 2012;37(2):199–207.
38. Das A, Heesters BA, Bialas A, et al. Follicular dendritic cell activation by TLR ligands promotes autoreactive B cell
responses. Immunity. 2017;46(1):106–19.
39. Kosco‑Vilbois MH. Are follicular dendritic cells really good for nothing? Nat Rev Immunol. 2003;3(9):764–9.
Page 23 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
40. Heesters BA, Myers RC, Carroll MC. Follicular dendritic cells: dynamic antigen libraries. Nat Rev Immunol.
2014;14(7):495–504.
41. Heesters BA, Chatterjee P, Kim YA, et al. Endocytosis and recycling of immune complexes by follicular dendritic
cells enhances B cell antigen binding and activation. Immunity. 2013;38(6):1164–75.
42. Flohé SB, Agrawal H, Schmitz D, Gertz M, Flohé S, Schade FU. Dendritic cells during polymicrobial sepsis rapidly
mature but fail to initiate a protective Th1‑type immune response. J Leukoc Biol. 2006;79(3):473–81.
43. Le Tulzo Y, Pangault C, Amiot L, et al. Monocyte human leukocyte antigen‑DR transcriptional downregulation by
cortisol during septic shock. Am J Respir Crit Care Med. 2004;169(10):1144–51.
44. Fan X, Liu Z, Jin H, Yan J, Liang HP. Alterations of dendritic cells in sepsis: featured role in immunoparalysis. Biomed
Res Int. 2015;2015:903720.
45. Benjamim CF, Lundy SK, Lukacs NW, Hogaboam CM, Kunkel SL. Reversal of long‑term sepsis‑induced immunosup‑
pression by dendritic cells. Blood. 2005;105(9):3588–95.
46. Pastille E, Didovic S, Brauckmann D, et al. Modulation of dendritic cell differentiation in the bone marrow mediates
sustained immunosuppression after polymicrobial sepsis. J Immunol. 2011;186(2):977–86.
47. Venet F, Demaret J, Gossez M, Monneret G. Myeloid cells in sepsis‑acquired immunodeficiency. Ann N Y Acad Sci.
2021;1499(1):3–17.
48. Steinbrink K, Graulich E, Kubsch S, Knop J, Enk AH. CD4+ and CD8+ anergic T cells induced by interleukin‑
10‑treated human dendritic cells display antigen‑specific suppressor activity. Blood. 2002;99(7):2468–76.
49. Luan YY, Dong N, Xie M, Xiao XZ, Yao YM. The significance and regulatory mechanisms of innate immune cells in
the development of sepsis. J Interferon Cytokine Res. 2014;34(1):2–15.
50. Li JY, Ren C, Wang LX, et al. Sestrin2 protects dendrite cells against ferroptosis induced by sepsis. Cell Death Dis.
2021;12(9):834.
51. Lu J, Sun K, Yang H, et al. Sepsis inflammation impairs the generation of functional dendritic cells by targeting
their progenitors. Front Immunol. 2021;12:732612.
52. Riccardi F, Della Porta MG, Rovati B, et al. Flow cytometric analysis of peripheral blood dendritic cells in patients
with severe sepsis. Cytometry B Clin Cytom. 2011;80(1):14–21.
53. Faivre V, Lukaszewicz AC, Alves A, Charron D, Payen D, Haziot A. Accelerated in vitro differentiation of blood mono‑
cytes into dendritic cells in human sepsis. Clin Exp Immunol. 2007;147(3):426–39.
54. Faivre V, Lukaszewicz AC, Alves A, Charron D, Payen D, Haziot A. Human monocytes differentiate into dendritic
cells subsets that induce anergic and regulatory T cells in sepsis. PLoS ONE. 2012;7(10): e47209.
55. Zhu XM, Dong N, Wang YB, et al. The involvement of endoplasmic reticulum stress response in immune dysfunc‑
tion of dendritic cells after severe thermal injury in mice. Oncotarget. 2017;8(6):9035–52.
56. Luan YY, Zhang L, Zhu FJ, Dong N, Lu JY, Yao YM. Effect of TIPE1 on immune function of dendritic cells and its
signaling pathway in septic mice. J Infect Dis. 2019;220(4):699–709.
57. Liu SQ, Ren C, Yao RQ, et al. TNF‑alpha‑induced protein 8‑like 2 negatively regulates the immune function of den‑
dritic cells by suppressing autophagy via the TAK1/JNK pathway in septic mice. Cell Death Dis. 2021;12(11):1032.
58. Wu Y, Chen L, Qiu Z, Zhang X, Zhao G, Lu Z. PINK1 protects against dendritic cell dysfunction during sepsis
through the regulation of mitochondrial quality control. Mol Med. 2023;29(1):25.
59. Pène F, Courtine E, Ouaaz F, et al. Toll‑like receptors 2 and 4 contribute to sepsis‑induced depletion of spleen
dendritic cells. Infect Immun. 2009;77(12):5651–8.
60. Hotchkiss RS, Tinsley KW, Swanson PE, et al. Depletion of dendritic cells, but not macrophages, in patients with
sepsis. J Immunol. 2002;168(5):2493–500.
61. D’Arpa N, Accardo‑Palumbo A, Amato G, et al. Circulating dendritic cells following burn. Burns. 2009;35(4):513–8.
62. Efron PA, Martins A, Minnich D, et al. Characterization of the systemic loss of dendritic cells in murine lymph nodes
during polymicrobial sepsis. J Immunol. 2004;173(5):3035–43.
63. Boomer JS, To K, Chang KC, et al. Immunosuppression in patients who die of sepsis and multiple organ failure.
JAMA. 2011;306(23):2594–605.
64. Barthelemy A, Ivanov S, Fontaine J, et al. Influenza A virus‑induced release of interleukin‑10 inhibits the anti‑micro‑
bial activities of invariant natural killer T cells during invasive pneumococcal superinfection. Mucosal Immunol.
2017;10(2):460–9.
65. Beshara R, Sencio V, Soulard D, et al. Alteration of Flt3‑Ligand‑dependent de novo generation of conventional
dendritic cells during influenza infection contributes to respiratory bacterial superinfection. PLoS Pathog.
2018;14(10): e1007360.
66. Hotchkiss RS, Chang KC, Swanson PE, et al. Caspase inhibitors improve survival in sepsis: a critical role of the
lymphocyte. Nat Immunol. 2000;1(6):496–501.
67. Ding Y, Chung CS, Newton S, et al. Polymicrobial sepsis induces divergent effects on splenic and peritoneal den‑
dritic cell function in mice. Shock. 2004;22(2):137–44.
68. Tinsley KW, Grayson MH, Swanson PE, et al. Sepsis induces apoptosis and profound depletion of splenic interdigi‑
tating and follicular dendritic cells. J Immunol. 2003;171(2):909–14.
69. Li P, Zhao R, Fan K, et al. Regulation of dendritic cell function improves survival in experimental sepsis through
immune chaperone. Innate Immun. 2019;25(4):235–43.
70. Galluzzi L, Vitale I, Aaronson SA, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature
Committee on Cell Death 2018. Cell Death Differ. 2018;25(3):486–541.
71. Fernald K, Kurokawa M. Evading apoptosis in cancer. Trends Cell Biol. 2013;23(12):620–33.
72. Wesche‑Soldato DE, Lomas‑Neira JL, Perl M, Jones L, Chung CS, Ayala A. The role and regulation of apoptosis in
sepsis. J Endotoxin Res. 2005;11(6):375–82.
73. Luan YY, Yao YM, Xiao XZ, Sheng ZY. Insights into the apoptotic death of immune cells in sepsis. J Interferon
Cytokine Res. 2015;35(1):17–22.
74. Gautier EL, Huby T, Saint‑Charles F, Ouzilleau B, Chapman MJ, Lesnik P. Enhanced dendritic cell survival attenuates
lipopolysaccharide‑induced immunosuppression and increases resistance to lethal endotoxic shock. J Immunol.
2008;180(10):6941–6.
Page 24 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
75. Peck‑Palmer OM, Unsinger J, Chang KC, et al. Modulation of the Bcl‑2 family blocks sepsis‑induced depletion of
dendritic cells and macrophages. Shock. 2009;31(4):359–66.
76. Falcone S, Perrotta C, De Palma C, et al. Activation of acid sphingomyelinase and its inhibition by the nitric oxide/
cyclic guanosine 3′,5′‑monophosphate pathway: key events in Escherichia coli‑elicited apoptosis of dendritic
cells. J Immunol. 2004;173(7):4452–63.
77. Zhang L, Cardinal JS, Pan P, et al. Splenocyte apoptosis and autophagy is mediated by interferon regulatory factor
1 during murine endotoxemia. Shock. 2012;37(5):511–7.
78. Zanoni I, Ostuni R, Capuano G, et al. CD14 regulates the dendritic cell life cycle after LPS exposure through NFAT
activation. Nature. 2009;460(7252):264–8.
79. Bertheloot D, Latz E, Franklin BS. Necroptosis, pyroptosis and apoptosis: an intricate game of cell death. Cell Mol
Immunol. 2021;18(5):1106–21.
80. Maeda A, Fadeel B. Mitochondria released by cells undergoing TNF‑α‑induced necroptosis act as danger signals.
Cell Death Dis. 2014;5(7): e1312.
81. Kaczmarek A, Vandenabeele P, Krysko DV. Necroptosis: the release of damage‑associated molecular patterns and
its physiological relevance. Immunity. 2013;38(2):209–23.
82. Duprez L, Takahashi N, Van Hauwermeiren F, et al. RIP kinase‑dependent necrosis drives lethal systemic inflamma‑
tory response syndrome. Immunity. 2011;35(6):908–18.
83. Newton K, Dugger DL, Maltzman A, et al. RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit
than MLKL deficiency in mouse models of inflammation and tissue injury. Cell Death Differ. 2016;23(9):1565–76.
84. Wu J, Huang Z, Ren J, et al. Mlkl knockout mice demonstrate the indispensable role of Mlkl in necroptosis. Cell Res.
2013;23(8):994–1006.
85. Liu Y, Xu Q, Wang Y, et al. Necroptosis is active and contributes to intestinal injury in a piglet model with lipopoly‑
saccharide challenge. Cell Death Dis. 2021;12(1):62.
86. Xu Q, Guo J, Li X, et al. Necroptosis underlies hepatic damage in a piglet model of lipopolysaccharide‑induced
sepsis. Front Immunol. 2021;12: 633830.
87. Siempos II, Ma KC, Imamura M, et al. RIPK3 mediates pathogenesis of experimental ventilator‑induced lung injury.
JCI Insight. 2018;3(9): e97102.
88. Nakamura H, Kinjo T, Arakaki W, Miyagi K, Tateyama M, Fujita J. Serum levels of receptor‑interacting protein
kinase‑3 in patients with COVID‑19. Crit Care. 2020;24(1):484.
89. Yoo H, Im Y, Ko RE, Lee JY, Park J, Jeon K. Association of plasma level of high‑mobility group box‑1 with necroptosis
and sepsis outcomes. Sci Rep. 2021;11(1):9512.
90. Yang X, Lu H, Xie H, et al. Potent and selective RIPK1 inhibitors targeting dual‑pockets for the treatment of sys‑
temic inflammatory response syndrome and sepsis. Angew Chem Int Ed Engl. 2022;61(5): e202114922.
91. Bolognese AC, Yang WL, Hansen LW, et al. Inhibition of necroptosis attenuates lung injury and improves survival in
neonatal sepsis. Surgery. 2018;164(1):110–6.
92. Huang MY, Wan DW, Deng J, et al. Downregulation of RIP3 improves the protective effect of ATF6 in an acute liver
injury model. Biomed Res Int. 2021;2021:8717565.
93. Linkermann A, Bräsen JH, De Zen F, et al. Dichotomy between RIP1‑ and RIP3‑mediated necroptosis in tumor
necrosis factor‑α‑induced shock. Mol Med. 2012;18(1):577–86.
94. Polykratis A, Hermance N, Zelic M, et al. Cutting edge: RIPK1 Kinase inactive mice are viable and protected from
TNF‑induced necroptosis in vivo. J Immunol. 2014;193(4):1539–43.
95. Raffray L, Douchet I, Augusto JF, et al. Septic shock sera containing circulating histones induce dendritic cell‑
regulated necrosis in fatal septic shock patients. Crit Care Med. 2015;43(4):e107–16.
96. McNeal SI, LeGolvan MP, Chung CS, Ayala A. The dual functions of receptor interacting protein 1 in fas‑induced
hepatocyte death during sepsis. Shock. 2011;35(5):499–505.
97. Vandenabeele P, Grootjans S, Callewaert N, Takahashi N. Necrostatin‑1 blocks both RIPK1 and IDO: consequences
for the study of cell death in experimental disease models. Cell Death Differ. 2013;20(2):185–7.
98. Takahashi N, Duprez L, Grootjans S, et al. Necrostatin‑1 analogues: critical issues on the specificity, activity and
in vivo use in experimental disease models. Cell Death Dis. 2012;3(11): e437.
99. Moreno‑Gonzalez G, Vandenabeele P, Krysko DV. Necroptosis: a novel cell death modality and its potential rel‑
evance for critical care medicine. Am J Respir Crit Care Med. 2016;194(4):415–28.
100. O’Donnell JA, Lehman J, Roderick JE, et al. Dendritic cell RIPK1 maintains immune homeostasis by preventing
inflammation and autoimmunity. J Immunol. 2018;200(2):737–48.
101. Frank D, Vince JE. Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ.
2019;26(1):99–114.
102. Zheng X, Chen W, Gong F, Chen Y, Chen E. The role and mechanism of pyroptosis and potential therapeutic
targets in sepsis: a review. Front Immunol. 2021;12:711939.
103. Qu M, Wang Y, Qiu Z, et al. Necroptosis, pyroptosis, ferroptosis in sepsis and treatment. Shock. 2022;57(6):161–71.
104. Wen R, Liu YP, Tong XX, Zhang TN, Yang N. Molecular mechanisms and functions of pyroptosis in sepsis and sepsis‑
associated organ dysfunction. Front Cell Infect Microbiol. 2022;12:962139.
105. Tang D, Kang R, Berghe TV, Vandenabeele P, Kroemer G. The molecular machinery of regulated cell death. Cell Res.
2019;29(5):347–64.
106. Fu Q, Wu J, Zhou XY, et al. NLRP3/caspase‑1 pathway‑induced pyroptosis mediated cognitive deficits in a mouse
model of sepsis‑associated encephalopathy. Inflammation. 2019;42(1):306–18.
107. Chen YL, Xu G, Liang X, et al. Inhibition of hepatic cells pyroptosis attenuates CLP‑induced acute liver injury. Am J
Transl Res. 2016;8(12):5685–95.
108. Wang YC, Liu QX, Zheng Q, et al. Dihydromyricetin alleviates sepsis‑induced acute lung injury through inhibiting
NLRP3 inflammasome‑dependent pyroptosis in mice model. Inflammation. 2019;42(4):1301–10.
109. Lee S, Nakahira K, Dalli J, et al. NLRP3 inflammasome deficiency protects against microbial sepsis via increased
lipoxin B4 synthesis. Am J Respir Crit Care Med. 2017;196(6):713–26.
Page 25 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
110. Kang R, Zeng L, Zhu S, et al. Lipid peroxidation drives gasdermin D‑mediated pyroptosis in lethal polymicrobial
sepsis. Cell Host Microbe. 2018;24(1):97‑108.e4.
111. Erlich Z, Shlomovitz I, Edry‑Botzer L, et al. Macrophages, rather than DCs, are responsible for inflammasome activ‑
ity in the GM‑CSF BMDC model. Nat Immunol. 2019;20(4):397–406.
112. Guermonprez P, Helft J. Inflammasome activation: a monocyte lineage privilege. Nat Immunol. 2019;20(4):383–5.
113. Wang LX, Ren C, Yao RQ, et al. Sestrin2 protects against lethal sepsis by suppressing the pyroptosis of dendritic
cells. Cell Mol Life Sci. 2021;78(24):8209–27.
114. Menu P, Mayor A, Zhou R, et al. ER stress activates the NLRP3 inflammasome via an UPR‑independent pathway.
Cell Death Dis. 2012;3(1): e261.
115. Chen X, Guo X, Ge Q, Zhao Y, Mu H, Zhang J. ER stress activates the NLRP3 inflammasome: a novel mechanism of
atherosclerosis. Oxid Med Cell Longev. 2019;2019:3462530.
116. Zanoni I, Tan Y, Di Gioia M, et al. An endogenous caspase‑11 ligand elicits interleukin‑1 release from living den‑
dritic cells. Science. 2016;352(6290):1232–6.
117. Kumari P, Russo AJ, Wright SS, Muthupalani S, Rathinam VA. Hierarchical cell‑type‑specific functions of caspase‑11
in LPS shock and antibacterial host defense. Cell Rep. 2021;35(3):109012.
118. Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol.
2021;22(4):266–82.
119. Chen X, Kang R, Kroemer G, Tang D. Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol.
2021;18(5):280–96.
120. Zheng J, Conrad M. The metabolic underpinnings of ferroptosis. Cell Metab. 2020;32(6):920–37.
121. Liu Y, Tan S, Wu Y, Tan S. The emerging role of ferroptosis in sepsis. DNA Cell Biol. 2022;41(4):368–80.
122. Lei XL, Zhao GY, Guo R, Cui N. Ferroptosis in sepsis: the mechanism, the role and the therapeutic potential. Front
Immunol. 2022;13:956361.
123. Li J, Li M, Li L, Ma J, Yao C, Yao S. Hydrogen sulfide attenuates ferroptosis and stimulates autophagy by blocking
mTOR signaling in sepsis‑induced acute lung injury. Mol Immunol. 2022;141:318–27.
124. Li N, Wang W, Zhou H, et al. Ferritinophagy‑mediated ferroptosis is involved in sepsis‑induced cardiac injury. Free
Radic Biol Med. 2020;160:303–18.
125. Wang C, Yuan W, Hu A, et al. Dexmedetomidine alleviated sepsis induced myocardial ferroptosis and septic heart
injury. Mol Med Rep. 2020;22(1):175–84.
126. Wei S, Bi J, Yang L, et al. Serum irisin levels are decreased in patients with sepsis, and exogenous irisin suppresses
ferroptosis in the liver of septic mice. Clin Transl Med. 2020;10(5): e173.
127. Liu X, Wang L, Xing Q, et al. Sevoflurane inhibits ferroptosis: a new mechanism to explain its protective role against
lipopolysaccharide‑induced acute lung injury. Life Sci. 2021;275:119391.
128. Li J, Lu K, Sun F, et al. Panaxydol attenuates ferroptosis against LPS‑induced acute lung injury in mice by Keap1‑
Nrf2/HO‑1 pathway. J Transl Med. 2021;19(1):96.
129. Xiao Z, Kong B, Fang J, et al. Ferrostatin‑1 alleviates lipopolysaccharide‑induced cardiac dysfunction. Bioengi‑
neered. 2021;12(2):9367–76.
130. Brandtner A, Tymoszuk P, Nairz M, et al. Linkage of alterations in systemic iron homeostasis to patients’ outcome in
sepsis: a prospective study. J Intensive Care. 2020;8:76.
131. Liu W, Xu C, Zou Z, Weng Q, Xiao Y. Sestrin2 suppresses ferroptosis to alleviate septic intestinal inflammation and
barrier dysfunction. Immunopharmacol Immunotoxicol. 2023;45(2):123–32.
132. Denton D, Kumar S. Autophagy‑dependent cell death. Cell Death Differ. 2019;26(4):605–16.
133. Doherty J, Baehrecke EH. Life, death and autophagy. Nat Cell Biol. 2018;20(10):1110–7.
134. Liu S, Yao S, Yang H, Liu S, Wang Y. Autophagy: regulator of cell death. Cell Death Dis. 2023;14(10):648.
135. Nah J, Zablocki D, Sadoshima J. Autosis: a new target to prevent cell death. JACC Basic Transl Sci. 2020;5(8):857–69.
136. Liu Y, Levine B. Autosis and autophagic cell death: the dark side of autophagy. Cell Death Differ. 2015;22(3):367–76.
137. Bialik S, Dasari SK, Kimchi A. Autophagy‑dependent cell death—where, how and why a cell eats itself to death. J
Cell Sci. 2018;131(18): jcs215152.
138. Zein L, Fulda S, Kögel D, van Wijk SJL. Organelle‑specific mechanisms of drug‑induced autophagy‑dependent cell
death. Matrix Biol. 2021;100–101:54–64.
139. Hsieh YC, Athar M, Chaudry IH. When apoptosis meets autophagy: deciding cell fate after trauma and sepsis.
Trends Mol Med. 2009;15(3):129–38.
140. Schmid D, Pypaert M, Münz C. Antigen‑loading compartments for major histocompatibility complex class II
molecules continuously receive input from autophagosomes. Immunity. 2007;26(1):79–92.
141. Ghislat G, Lawrence T. Autophagy in dendritic cells. Cell Mol Immunol. 2018;15(11):944–52.
142. Weindel CG, Richey LJ, Mehta AJ, Shah M, Huber BT. Autophagy in dendritic cells and B cells is critical for the
inflammatory state of TLR7‑mediated autoimmunity. J Immunol. 2017;198(3):1081–92.
143. Zhang Y, Chen L, Luo Y, et al. Pink1/parkin‑mediated mitophagy regulated the apoptosis of dendritic cells in sepsis.
Inflammation. 2022;45(3):1374–87.
144. Zhou B, Liu J, Kang R, Klionsky DJ, Kroemer G, Tang D. Ferroptosis is a type of autophagy‑dependent cell death.
Semin Cancer Biol. 2020;66:89–100.
145. Lin SY, Hsieh SY, Fan YT, et al. Necroptosis promotes autophagy‑dependent upregulation of DAMP and results in
immunosurveillance. Autophagy. 2018;14(5):778–95.
146. Kist M, Vucic D. Cell death pathways: intricate connections and disease implications. EMBO J. 2021;40(5): e106700.
147. Zhao PY, Yao RQ, Zheng LY, et al. Nuclear fragile X mental retardation‑interacting protein 1‑mediated ribophagy
protects T lymphocytes against apoptosis in sepsis. Burns Trauma. 2023;11(1): tkac055.
148. Wu J, Ye J, Xie Q, Liu B, Liu M. Targeting regulated cell death with pharmacological small molecules: an update on
autophagy‑dependent cell death, ferroptosis, and necroptosis in cancer. J Med Chem. 2022;65(4):2989–3001.
149. Kriel J, Loos B. The good, the bad and the autophagosome: exploring unanswered questions of autophagy‑
dependent cell death. Cell Death Differ. 2019;26(4):640–52.
Page 26 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
150. Wang G, Li X, Zhang L, Elgaili Abdalla A, Teng T, Li Y. Crosstalk between dendritic cells and immune modulatory
agents against sepsis. Genes. 2020;11(3):323.
151. Torres LK, Pickkers P, van der Poll T. Sepsis‑induced immunosuppression. Annu Rev Physiol. 2022;84:157–81.
152. Li CC, Munitic I, Mittelstadt PR, Castro E, Ashwell JD. Suppression of dendritic cell‑derived IL‑12 by endogenous
glucocorticoids is protective in LPS‑induced sepsis. PLoS Biol. 2015;13(10): e1002269.
153. Patel R, Bookout AL, Magomedova L, et al. Glucocorticoids regulate the metabolic hormone FGF21 in a feed‑
forward loop. Mol Endocrinol. 2015;29(2):213–23.
154. Xiao Y, Yan W, Zhou K, Cao Y, Cai W. Glucocorticoid treatment alters systemic bile acid homeostasis by regulating
the biosynthesis and transport of bile salts. Dig Liver Dis. 2016;48(7):771–9.
155. Ren R, Oakley RH, Cruz‑Topete D, Cidlowski JA. Dual role for glucocorticoids in cardiomyocyte hypertrophy and
apoptosis. Endocrinology. 2012;153(11):5346–60.
156. Robinson R. Glucocorticoids reduce sepsis by diminishing dendritic cell responses. PLoS Biol. 2015;13(10):
e1002270.
157. Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of
sepsis and septic shock 2021. Intensive Care Med. 2021;47(11):1181–247.
158. Keh D, Trips E, Marx G, et al. Effect of hydrocortisone on development of shock among patients with severe sepsis:
the HYPRESS randomized clinical trial. JAMA. 2016;316(17):1775–85.
159. Annane D, Renault A, Brun‑Buisson C, et al. Hydrocortisone plus fludrocortisone for adults with septic shock. N
Engl J Med. 2018;378(9):809–18.
160. Choi K, Park JE, Kim A, et al. The DEXA‑SEPSIS study protocol: a phase II randomized double‑blinded controlled trial
of the effect of early dexamethasone in high‑risk sepsis patients. Clin Exp Emerg Med. 2022;9(3):246–52.
161. Serafino A, Pierimarchi P, Pica F, et al. Thymosin α1 as a stimulatory agent of innate cell‑mediated immune
response. Ann N Y Acad Sci. 2012;1270:13–20.
162. Yao Q, Doan LX, Zhang R, Bharadwaj U, Li M, Chen C. Thymosin‑alpha1 modulates dendritic cell differentiation and
functional maturation from human peripheral blood CD14+ monocytes. Immunol Lett. 2007;110(2):110–20.
163. Romani L, Bistoni F, Gaziano R, et al. Thymosin alpha 1 activates dendritic cells for antifungal Th1 resistance
through toll‑like receptor signaling. Blood. 2004;103(11):4232–9.
164. Romani L, Bistoni F, Montagnoli C, et al. Thymosin alpha1: an endogenous regulator of inflammation, immunity,
and tolerance. Ann N Y Acad Sci. 2007;1112:326–38.
165. Pei F, Guan XD, Wu JF. Thymosin alpha 1 treatment for patients with sepsis. Expert Opin Biol Ther. 2018;18(Suppl
1):71–6.
166. Deng M, Ma T, Yan Z, et al. Toll‑like receptor 4 signaling on dendritic cells suppresses polymorphonuclear
leukocyte CXCR2 expression and trafficking via interleukin 10 during intra‑abdominal sepsis. J Infect Dis.
2016;213(8):1280–8.
167. Barrenschee M, Lex D, Uhlig S. Effects of the TLR2 agonists MALP‑2 and Pam3Cys in isolated mouse lungs. PLoS
ONE. 2010;5(11): e13889.
168. Perrin‑Cocon L, Aublin‑Gex A, Sestito SE, et al. TLR4 antagonist FP7 inhibits LPS‑induced cytokine production
and glycolytic reprogramming in dendritic cells, and protects mice from lethal influenza infection. Sci Rep.
2017;7:40791.
169. Opal SM, Laterre PF, Francois B, et al. Effect of eritoran, an antagonist of MD2‑TLR4, on mortality in patients with
severe sepsis: the ACCESS randomized trial. JAMA. 2013;309(11):1154–62.
170. Baumann CL, Aspalter IM, Sharif O, et al. CD14 is a coreceptor of Toll‑like receptors 7 and 9. J Exp Med.
2010;207(12):2689–701.
171. Lee HK, Dunzendorfer S, Soldau K, Tobias PS. Double‑stranded RNA‑mediated TLR3 activation is enhanced by
CD14. Immunity. 2006;24(2):153–63.
172. Raby AC, Holst B, Le Bouder E, et al. Targeting the TLR co‑receptor CD14 with TLR2‑derived peptides modulates
immune responses to pathogens. Sci Transl Med. 2013;5(185):185ra64.
173. Atalan N, Acar L, Yapici N, et al. The relationship between sepsis‑induced immunosuppression and serum Toll‑like
receptor 9 level. In Vivo. 2018;32(6):1653–8.
174. Tan TL, Goh YY. The role of group IIA secretory phospholipase A2 (sPLA2‑IIA) as a biomarker for the diagnosis of
sepsis and bacterial infection in adults: a systematic review. PLoS ONE. 2017;12(7): e0180554.
175. Perrin‑Cocon L, Agaugué S, Coutant F, et al. Secretory phospholipase A2 induces dendritic cell maturation. Eur J
Immunol. 2004;34(8):2293–302.
176. Bae JS. Role of high mobility group box 1 in inflammatory disease: focus on sepsis. Arch Pharm Res.
2012;35(9):1511–23.
177. Zhu XM, Yao YM, Liang HP, et al. The effect of high mobility group box‑1 protein on splenic dendritic cell matura‑
tion in rats. J Interferon Cytokine Res. 2009;29(10):677–86.
178. Zhang LT, Yao YM, Yao FH, et al. Association between high‑mobility group box‑1 protein release and immune
function of dendritic cells in thermal injury. J Interferon Cytokine Res. 2010;30(7):487–95.
179. Ye C, Choi JG, Abraham S, et al. Human macrophage and dendritic cell‑specific silencing of high‑mobility group
protein B1 ameliorates sepsis in a humanized mouse model. Proc Natl Acad Sci USA. 2012;109(51):21052–7.
180. Brück E, Svensson‑Raskh A, Larsson JW, et al. Plasma HMGB1 levels and physical performance in ICU survivors. Acta
Anaesthesiol Scand. 2021;65(7):921–7.
181. Ma N, Xing C, Xiao H, et al. C5a regulates IL‑12+ DC migration to induce pathogenic Th1 and Th17 cells in sepsis.
PLoS ONE. 2013;8(7): e69779.
182. Rittirsch D, Flierl MA, Nadeau BA, et al. Functional roles for C5a receptors in sepsis. Nat Med. 2008;14(5):551–7.
183. Riedemann NC, Guo RF, Hollmann TJ, et al. Regulatory role of C5a in LPS‑induced IL‑6 production by neutrophils
during sepsis. FASEB J. 2004;18(2):370–2.
184. Mollnes TE, Brekke OL, Fung M, et al. Essential role of the C5a receptor in E. coli‑induced oxidative burst
and phagocytosis revealed by a novel lepirudin‑based human whole blood model of inflammation. Blood.
2002;100(5):1869–77.
Page 27 of 27
Zhengetal. Cellular & Molecular Biology Letters (2024) 29:81
185. Given WP, Edelson HS, Kaplan HB, Aisen P, Weissmann G, Abramson SB. Generation of C5‑derived peptides
and other immune reactants in the sera of patients with systemic lupus erythematosus. Arthritis Rheum.
1984;27(6):631–7.
186. Strainic MG, Shevach EM, An F, Lin F, Medof ME. Absence of signaling into CD4+ cells via C3aR and C5aR enables
autoinductive TGF‑β1 signaling and induction of Foxp3+ regulatory T cells. Nat Immunol. 2013;14(2):162–71.
187. Grailer JJ, Fattahi F, Dick RS, Zetoune FS, Ward PA. Cutting edge: critical role for C5aRs in the development of septic
lymphopenia in mice. J Immunol. 2015;194(3):868–72.
188. Flierl MA, Rittirsch D, Chen AJ, et al. The complement anaphylatoxin C5a induces apoptosis in adrenomedullary
cells during experimental sepsis. PLoS ONE. 2008;3(7): e2560.
189. Huber‑Lang MS, Younkin EM, Sarma JV, et al. Complement‑induced impairment of innate immunity during sepsis.
J Immunol. 2002;169(6):3223–31.
190. Riedemann NC, Guo RF, Laudes IJ, et al. C5a receptor and thymocyte apoptosis in sepsis. FASEB J. 2002;16(8):887–8.
191. Schefold JC, von Haehling S, Corsepius M, et al. A novel selective extracorporeal intervention in sepsis: immunoad‑
sorption of endotoxin, interleukin 6, and complement‑activating product 5a. Shock. 2007;28(4):418–25.
192. Sun Y, Varambally S, Maher CA, et al. Targeting of microRNA‑142‑3p in dendritic cells regulates endotoxin‑induced
mortality. Blood. 2011;117(23):6172–83.
193. Park H, Huang X, Lu C, Cairo MS, Zhou X. MicroRNA‑146a and microRNA‑146b regulate human dendritic cell
apoptosis and cytokine production by targeting TRAF6 and IRAK1 proteins. J Biol Chem. 2015;290(5):2831–41.
194. Lu C, Huang X, Zhang X, et al. miR‑221 and miR‑155 regulate human dendritic cell development, apoptosis, and
IL‑12 production through targeting of p27kip1, KPC1, and SOCS‑1. Blood. 2011;117(16):4293–303.
195. Su L, Pan P, Yan P, et al. Role of vimentin in modulating immune cell apoptosis and inflammatory responses in
sepsis. Sci Rep. 2019;9(1):5747.
196. Nakashima T, Miyamoto K, Shima N, et al. Dexmedetomidine improved renal function in patients with severe
sepsis: an exploratory analysis of a randomized controlled trial. J Intensive Care. 2020;8:1.
197. Ohta Y, Miyamoto K, Kawazoe Y, Yamamura H, Morimoto T. Effect of dexmedetomidine on inflammation in
patients with sepsis requiring mechanical ventilation: a sub‑analysis of a multicenter randomized clinical trial. Crit
Care. 2020;24(1):493.
198. Kawazoe Y, Miyamoto K, Morimoto T, et al. Effect of dexmedetomidine on mortality and ventilator‑free days in
patients requiring mechanical ventilation with sepsis: a randomized clinical trial. JAMA. 2017;317(13):1321–8.
199. Yao RQ, Zhao PY, Li ZX, et al. Single‑cell transcriptome profiling of sepsis identifies HLA‑DRlowS100Ahigh monocytes
with immunosuppressive function. Mil Med Res. 2023;10(6):27.
200. Pei F, Yao RQ, Ren C, et al. Expert consensus on the monitoring and treatment of sepsis‑induced immunosuppres‑
sion. Mil Med Res. 2022;9(1):74.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
