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Tryptophan Catabolism and
Inflammation: A Novel Therapeutic
Target For Aortic Diseases
Tharmarajan Ramprasath, Young-Min Han, Donghong Zhang, Chang-Jiang Yu
and Ming-Hui Zou*
Center for Molecular and Translational Medicine, Georgia State University, Atlanta, GA, United States
Aortic diseases are the primary public health concern. As asymptomatic diseases,
abdominal aortic aneurysm (AAA) and atherosclerosis are associated with high
morbidity and mortality. The inflammatory process constitutes an essential part of a
pathogenic cascade of aortic diseases, including atherosclerosis and aortic aneurysms.
Inflammation on various vascular beds, including endothelium, smooth muscle cell
proliferation and migration, and inflammatory cell infiltration (monocytes, macrophages,
neutrophils, etc.), play critical roles in the initiation and progression of aortic diseases. The
tryptophan (Trp) metabolism or kynurenine pathway (KP) is the primary way of degrading
Trp in most mammalian cells, disturbed by cytokines under various stress. KP generates
several bioactive catabolites, such as kynurenine (Kyn), kynurenic acid (KA), 3-
hydroxykynurenine (3-HK), etc. Depends on the cell types, these metabolites can elicit
both hyper- and anti-inflammatory effects. Accumulating evidence obtained from various
animal disease models indicates that KP contributes to the inflammatory process during
the development of vascular disease, notably atherosclerosis and aneurysm
development. This review outlines current insights into how perturbed Trp metabolism
instigates aortic inflammation and aortic disease phenotypes. We also briefly highlight how
targeting Trp metabolic pathways should be considered for treating aortic diseases.
Keywords: aortic aneurysm, atherosclerosis, kynurenine pathway, tryptophan metabolism, vascular cells
Abbreviations: 3-HAA, 3-hydroxyanthranilic acid; 3-HK, 3-hydroxykynurenine; AA, anthranilic acid; AAA, Abdominal
aortic aneurysm; AhR, aryl hydrocarbon receptor; AngII, Angiotensin II; Apoe, Apolipoprotein E; BAPN, b-
Aminopropionitrile monofumarate; BH
4
, tetrahydrobiopterin; CAD, coronary artery disease; EC, endothelial cells; ECM,
extracellular matrix; eNOS, endothelial nitric oxide synthase; H3K9me3, Histone 3 lysine 9 trimethylation; HAAO, 3‐
hydroxyanthranilic acid dioxygenase; HFD, high fat diet; IDO, Indoleamine 2, 3-dioxygenase; IFNg, interferon-gamma; IL-1,
interleukin 1; IL-6, interleukin 6; KA, kynurenic acid; KAT, kynurenine aminotransferase; KMO, Kynurenine-3-
monooxygenase; KP, Kynurenine pathway; Kyn, kynurenine; Kynu, kynureninase; Ldlr, low-density lipoprotein receptor;
LKO, L-selectin-knockout mice; LPS, lipopolysaccharide; MDDCs, monocyte-derived DCs; MMP, Matrix metalloproteinase;
m-NBA, Nitrobenzoylalanine; NAD
+
, Nicotinamide adenine dinucleotide
+
; NETs, neutrophil extracellular traps; NF-kB,
nuclear factor kappa-B; NLPR2, Nod-like receptor protein 2; NO, nitric oxide; NOX, NADPH oxidase; O−
2, superoxide; O-
MBA, ortho methoxy benzoyl alanine; pDC, Plasmacytoid dendritic cells; PMN, polymorphonuclear neutrophils; PVAT,
perivascular aortic tissue; QA, quinolinic acid; QPRT, Quinolinate phosphoribosyl transferase; SPR, Sepiapterin reductase;
TAA, Thoracic aortic aneurysm; TDO, tryptophan-2,3-dioxygenase; TGF-b, transforming growth factor-b; TLR2, Toll-like
receptor 2; TNFa, tumor necrosis factor-alpha; Trp, Tryptophan; VSMC, vascular smooth muscle cells; XA, xanthurenic acid
Frontiers in Immunology | www.frontiersin.org September 2021 | Volume 12 | Article 7317011
Edited by:
La
´szlo
´Ve
´csei,
University of Szeged, Hungary
Reviewed by:
Andrea Baragetti,
University of Milan, Italy
Yutian Li,
University of Cincinnati, United States
*Correspondence:
Ming-Hui Zou
mzou@gsu.edu
Specialty section:
This article was submitted to
Inflammation,
a section of the journal
Frontiers in Immunology
Received: 28 June 2021
Accepted: 03 September 2021
Published: 23 September 2021
Citation:
Ramprasath T, Han Y-M, Zhang D,
Yu C-J and Zou M-H (2021)
Tryptophan Catabolism and
Inflammation: A Novel
Therapeutic Target
For Aortic Diseases.
Front. Immunol. 12:731701.
doi: 10.3389/fimmu.2021.731701
REVIEW
published: 23 September 2021
doi: 10.3389/fimmu.2021.731701
INTRODUCTION
Aortic diseases are the primary public health concern caused by
age, genetics, diabetes, obesity, sedentary lifestyle, infection and
injury. A slow and gradual thickening of the arteries, otherwise
called atherosclerosis, is the common cause of cardiovascular
diseases. Further, human arteries become less flexible with
increased ages, leading to aortic stiffness or a partially dilated
artery called aneurysm. Being asymptomatic, abdominal aortic
aneurysm (AAA) is a common and potentially life-threatening
condition as it may lead to rupture. However, elective aortic
surgery is also associated with risks; elective repair of the
aneurysm is the only way to prevent rupture. Thus, this
condition requires improved pharmacologic interventions,
which lacks in this modern medical system.
INFLAMMATION AND AORTIC DISEASES
(ATHEROSCLEROSIS AND AAA)
Atherosclerosis and AAAs are multifactorial and polygenic
diseases with known environmental and genetic risk factors
contributing to disease development (1,2). Atherosclerosis is a
chronic progressive inflammatory disorder that presents with
coronary artery disease (CAD) (3). CAD accounts for
approximately 610,000 deaths annually (estimated 1 in 4
deaths) and is the leading cause of mortality in the United
States (3). AAAs are majorly caused by aging, hypertension,
nicotine usage and atherosclerosis (4). Traditionally plenty of
evidence showed atherosclerosis as a common etiology for
thoracic aortic aneurysms (TAAs) and AAAs. AAA is a focal
progressive dilatation of the aorta with a diameter of at least 50%
greater than the average proximal diameter due to irreversible
structural aortic wall integrity loss. It is one of the significant
causes of worldwide morbidity and mortality that affects>1
million people in the United States alone (5). According to
CDC, AAAs were the cause of 9,923 deaths in 2018 in the
United States (6), and the mortality rate associated with AAA
rupture is 88%. Given the high mortality and morbidity related to
ruptured AAAs, this disease has traditionally posed a heavy
burden on healthcare systems (7), and there have been only
modest improvements in mortality over the last three decades.
The pathogenesis of AAA includes endothelial cell (EC)
dysfunction and vascular smooth muscle cells (VSMC)
apoptosis/senescence. Endothelial and VSMCs dysfunction
both can contribute to atherogenesis, which is widely accepted
(8,9). A variety of anti-inflammatory, antioxidant, beta-blockers
and hemodynamic modulator drugs and matrix
metalloproteinase (MMP) inhibitors are being studied to slow
aneurysm growth (9). However, there are no pharmacological
treatments available to either prevent or reverse the development
of AAA.
Our increasing knowledge suggests that inflammatory
processes are involved in the pathogenesis of aortic diseases
(10). An imbalance between the production and release of
proinflammatory factors has been reported in AAA’s pathology
(11) and atherosclerosis progression (12).Thenativeand
adaptive immune responses initiate and propagate the
inflammatory response to AAA pathology (13). During the
development of AAA, infiltration of many exogenous immune
cells, including lymphocytes, macrophages, mast cells,
neutrophils, and natural killer cells infiltrate gradually into the
tissue from adventitia to the intima, elicit a continuous
inflammatory response (10). The massive inflammatory cells
infiltration was interpreted in human aortic aneurysm surgical
samples. These infiltrations are usually absent among the healthy
aortic specimens. In AAA tissues, the B lymphocytes, T
lymphocytes and macrophages were majorly characterized cell
populations. Whereas the mast cells and natural killer cells were
characterized as minor cell populations in these AAA tissues
(14). These infiltrated Th1 mononuclear cells secrete the
cytokinessuchasIL-2,IFNg,andTNFa, to stimulate
proinflammatory osteopontin secretion from macrophages that
can propagate the inflammatory response during the AAA
development (15). Besides the immune cell infiltration, factors
released from dysfunctional perivascular aortic tissue (PVAT),
including several cytokines and adipokines, could also contribute
to arterial remodeling via immune activation.
TRYPTOPHAN/KYNURENINE
METABOLISM
L-Tryptophan (Trp) is an essential amino acid that should be
obtained from dietary intakes such as vegetal (potatoes,
chickpeas, soybeans, cocoa beans, and nuts) and animal origin
(dairy products, eggs, meat, and seafood) (16,17). The
tryptophan is so crucial for protein synthesis and thus it is
required for normal cellular homeostasis. It also serves as an in
vivo precursor for several bioactive compounds, including
nicotinamide (vitamin B6), serotonin, melatonin, tryptamine,
and kynurenines (18). Hepatic tryptophan-2,3-dioxygenase
(TDO) is known to play a critical role in keeping the
physiological concentrations of Trp and kynurenine (Kyn) at a
controlled level via kynurenine pathway (KP). In humans’serum
concentrations of Trp are in the range of 70 ± 10 µmol/L for
males and 65 ± 10 µmol/L for females and Kyn concentrations
are around 1.8 ± 0.4 µM and do not differ between genders (19).
Considering the KP metabolisms and their significant association
to many biological activities, the perturbations in the KP have
been linked to several diseases.
Two significant pathways that process Trp into other
metabolites are serotonin and kynurenine pathways. Most
dietary Trp (>95%) is fed into the KP, giving rise to several
downstream metabolites (19,20). The absolute and relative
concentrations of kynurenines vary among different cell types
due to different enzymatic repertoires (19). These Trp catabolites
are activated in times of stress and inflammation (21). Three
important rate-limiting enzymes indoleamine 2, 3-dioxygenase 1
and 2 (IDO1 and IDO2), and TDO utilize Trp as a substrate and
generate N-formylkynurenine during the initial steps on Trp
catabolism. This N-formylkynurenine is rapidly metabolized by
Ramprasath et al. Tryptophan Metabolism Links Aortic Diseases
Frontiers in Immunology | www.frontiersin.org September 2021 | Volume 12 | Article 7317012
formamidase into l-kynurenine (Kyn). Kyn is further catabolized
into several potent metabolites such as 3-hydroxykynurenine (3-
HK), 3-hydroxyanthranilic acid (3-HAA), kynurenic acid (KA),
and xanthurenic acid (XA), quinolinic acid (QA), and produce
the essential pyridine nucleotide end product, nicotinamide
adenine dinucleotide
+
(NAD
+
)(22). In brief, IDO produced
Kyn further catabolized by kynureninase (Kynu) produces
anthranilic acid (AA). Kynurenine-3-monooxygenase (KMO)
also converts Kyn into 3-HK, which is further utilized by
kynurenine aminotransferase (KAT) to produce XA or by the
Kynu to form 3-HAA. Further, 3-HAA is converted into
quinolinic acid (QA) or picolinic acid (PA) by a series of
enzymatic conversions. In addition, KAT metabolizes Kyn into
KA as well (Figure 1).
In hepatocytes TDO expression is stimulated by
glucocorticoids. In contrast, the IDO1 present outside the liver
is stimulated by proinflammatory cytokines (21). In the majority
of cell types, IDO expression is induced by proinflammatory
modulators, such as lipopolysaccharide (LPS), tumor necrosis
factor-a(TNFa), interleukin 1 (IL-1), and IL-2 (23,24). IDO
isoforms, (IDO1 and IDO2) closely linked on chromosome 8 in
humans, probably originating from an ancient gene duplication
(23,24). IDO1 is a heme-containing enzyme that catabolizes
compounds containing indole rings, such as the essential amino
acid Trp. The IDO1 isoform is expressed in various tissues,
including dendritic cells, endothelial cells, macrophages,
fibroblasts, and mesenchymal stromal cells, all are present in
the arterial wall. This major isoform contributes to Trp
degradation (25,26). Transport of the amino acid l-tryptophan
across the plasma membrane is known to occur through brush
border L-amino acid transporters (LATs) (27). A well-known
inducer interferon-gamma (IFN-g) released from activated
CD4+ T cells, robustly induces IDO1 expression contributing
to Trp catabolism. IFN-gcoordinately induces LATs to maximize
tryptophan depletion in IDO1-expressing cells and that the
process involves a positive feedback mechanism via
kynurenine-aryl hydrocarbon receptor (AhR) signaling (27).
The IDO2 isoform is primarily expressed in the kidney, brain,
colon, liver, and reproductive tract (25). Although the role of
IDO1 is widely studied, the function of IDO2 is largely
unexplored. Despite IDO1 and IDO2 exhibit critical functional
differences, IDO2 was characterized as having a weaker catalytic
activity than IDO1 in vitro (24). All these data strongly suggest
the importance of the tissue-specific expression and localization
of kynurenines producing proteins, which might regulate many
signaling pathways and the body’s physiological status.
TRYPTOPHAN METABOLISM,
INFLAMMATION AND AORTIC DISEASES
Tryptophan Metabolism and
Aortic Diseases
The altered amino acid metabolism and their metabolites were
observed in the plasma of patients with AAA. Untargeted
metabolic profiling of plasma showed statistically increased
concentrations of amino acid metabolites in the plasma of
people with large aneurysms when compared to the control
population. Thus, beyond contributing to protein synthesis,
amino acid metabolism plays a critical role in supporting
various cell functions (28–30), which is positively as well as
negatively correlated to vascular disease development. Among
many amino acids, l-Arginine (Arg), l-homoarginine (hArg), and
l-tryptophan (Trp) are important amino acids, and their
metabolites have a putative role in determining cardiovascular
diseases (31). For example, L-arginine, an essential amino acid,
improves endothelial function and cardiovascular health (32). It
is also known to alter inflammatory functions, and arginine
supplementation has wound healing potential by reducing
inflammation (33,34).
Lines of evidence suggest that IDO1 and the Kyn pathway
significantly contribute to cardiovascular diseases and thrombus
formation. The incidence, development, and progression of
vascular diseases are associated with body metabolism in
general. Very importantly, accumulating evidence shows that
Trp has a significant contribution to determine the AAA
FIGURE 1 | Tryptophan-Kynurenine and Serotonin Pathways. ~95% Trp is
transported into cytoplasm by LAT. In cytoplasm, tryptophan is initially
converted into kynurenine; Kynurenine into 3-Hydroxykynurenine by KMO; 3-
Hydroxykynurenine into 3-Hydroxyanthranilicacid and further quinolinic acid or
picolinic acid. In another axis, kynurenine is converted into kynurenic acid by
KAT. In another hand, tryptophan (~5%) is converted into serotonin by
serotonin pathway. 3-HK, 3-hydroxykynurenine; HAAO -3, hydroxyanthranilic
acid dioxygenase; IDO, Indoleamine 2, 3-dioxygenase; KAT, kynurenine
amino transferase; KAT, kynurenine amino transferase; KMO, kynurenine
monooxygenase; Kynu, kynureninase; LAT, L-amino acid transporters; PA,
picolinic acid; QA, quinolinic acid; QPRT, Quinolinate phosphoribosyl
transferase; TDO, tryptophan-2,3-dioxygenase; Trp-tryptophan.
Ramprasath et al. Tryptophan Metabolism Links Aortic Diseases
Frontiers in Immunology | www.frontiersin.org September 2021 | Volume 12 | Article 7317013
development. Trp metabolism, otherwise known as KP, is
dysregulated during vascular inflammation and many
cardiovascular diseases. A study conducted with the young
Finns population showed IDO enzyme’s involvement in the
immune regulation of early atherosclerosis (35). A significant
positive correlation of IDO activity in serum was observed
among the patients with more advanced atherosclerosis, which
suggest that activated KP may play a crucial role in vascular
diseases (36). We previously showed that angiotensin II (AngII)
infusion activates IFNgin immune cells, which induces the
expression of IDO1 and Kynu and increases 3-HAA
production in the plasma and aortas of (Apolipoprotein E)
Apoe
-/-
mice, but not in Apoe
-/-
IDO
-/-
mice (37). Silencing of
Kynu reduces the production of 3-HAA and further limits the
production of matrix metallopeptidase-2 (MMP2) in SMCs,
resulting in reduced AAA formation in Apoe
-/-
mice (37). We
also showed that AngII triggers the conversion of Trp to the
following product, 3-HK and activates the generation of NAD(P)
H oxidase (NOX)–mediated superoxide anions in endothelial
cells. The superoxide could accelerate the apoptotic process in
endothelial cells, leading to endothelial dysfunction (38). Kyn
also intensifies certain MMPs via the MEK-Erk1/2 signaling
pathway (39), which is important in vascular disease
development (40). Measurement of Trp degradation and the
product/substrate ratio (Kyn or 3-HK or 3-HAA/Trp) will
contribute to a better understanding of the interplay between
inflammation and vascular diseases (22). As above discussed, the
Trp metabolism is modulated by many risk factors during
vascular disease developments, which will be discussed with
more evidence in the following sections.
Inflammation Links KP Metabolism and
Aortic Diseases
Cytokines are crucial mediators of inflammation and essential
regulators of various immune and nonimmune cells in the aortic
wall. The expression of IDO2 is basal, whereas that of IDO1,
Kynu, etc, are induced by cytokines. A well-known cytokine is
IFNg, the most potent modulator of KP in vitro and in vivo
models and humans (41). Activated IDO along with activated
inflammatory parameters like IFNghave a positive correlation
with systemic chronic low-grade inflammation. However, LPS is
not a strong inducer, it is also known to induce IDO. These
findings reveal a direct link between the regulation of the KP and
inflammation under aortic disease conditions. However, the
functional contributions of secreted kynurenines by other cell
types including neutrophils, monocyte/macrophages, mast cells,
adipocytes, and platelets, remained to be determined. The
following sections will provide some evidence on the role of
these cells in aortic diseases and prove how kynurenine
metabolism affects the inflammatory process (Table 1).
Kynurenines Activate Inflammatory Genes
Kynwasshowntobeaproinflammatory metabolite. The
increased Kyn was accompanied by the Nod-like receptor
protein 2 (NLPR2) inflammasome expression and activation
(48). This was also evidenced by increased caspase-1
expression and IL-1brelease. After Kyn treatment, nuclear
factor kappa-B (NF-kB) could translocate into the nucleus and
binds to the promoter of NLRP2, subsequently increased NLRP2
transcription in vitro (48). To examine the IDO1 associated
transcription, a comparative transcriptome analysis was
performed between Ido1
-/-
and Ido1
+/+
rodent colon samples.
Transcriptome analyses revealed that absence of IDO1
significantly down-regulated the pathways involving TLR and
NF-kB signalings. Furthermore, dramatic changes in TLR and
NF-kB signaling resulted in substantial changes in the expression
of many inflammatory cytokines and chemokines (49). Similarly,
3-HK, and 3HAA both were reported to activate NF-kB signaling
and mediate the EC apoptosis and SMC senescence respectively
(37,38,50).
Many of the other kynurenines were also reported to
modulate AhR, both at transcriptional as well at activity levels.
AhR activation can influence inflammation and gene
transcription through cross-regulation of many inflammatory
signaling pathways. AhR activation was associated with
activation of Toll-like receptor 2 (TLR2) and its downstream of
NF-kB and the MAPKs, signaling pathways. Further, AhR
activation also promotes phosphorylation of p65/NF-kB, JNK/
MAPK, p38/MAPK, and ERK/MAPK pathways, which could
further promote production of pro-inflammatory mediators
including interleukin- 1b(IL-1b)andinterleukin-6(IL-6)
(51). Taken together these results demonstrate that the
kynurenines including Kyn, 3-HK, and 3HAA (37,38) are the
molecular regulators of inflammation that can influence
vascular inflammation.
TABLE 1 | Kynurenine metabolic members associated with aortic phenotype.
Aortic risk factors Altering catabolites Function Associated disease References
MMPs 3HAA ↑ECM degradation Aneurysm (37)
SMC apoptosis 3HAA ↑Cell inflammation Aneurysm (37)
EC apoptosis 3-HK ↑EC dysfunction Endothelial dysfunction (38)
ROS, NADPH activation 3-HK ↑Inhibits endothelial function Endothelial dysfunction (38)
Inhibition of BH
4
synthesis
XA ↑Inhibits BH
4
May impair NO synthesis (42,43)
Macrophage apoptosis 3HAA lowers plasma lipids and decreases atherosclerosis Decrease atherosclerosis (44)
EC function Kyn ↑Endothelium-derived relaxing factor Sepsis (45)
Atherosclerosis Kyn↑Suppression of T cells and possible protection against atherosclerosis. Atherosclerosis (46)
Atherosclerosis 3HAA 3HAA supplementation or HAAO inhibition both reduced atherosclerosis Atherosclerosis (47)
↑denotes “increased Level of particular catabolite”.
Ramprasath et al. Tryptophan Metabolism Links Aortic Diseases
Frontiers in Immunology | www.frontiersin.org September 2021 | Volume 12 | Article 7317014
KP REGULATION IN DIFFERENT
CELL TYPES
KP Regulation in Macrophages, Dendritic
Cells and Neutrophils
Numerous studies demonstrated the crucial roles of
inflammatory cells, including macrophages, dendritic cells and
neutrophils for their contribution to the development of AAA
(52). Aneurysm formation is associated with an accumulation of
macrophages within the adventitia and the media. Monocytes/
macrophages secrete TNFa,IFNgand IL-6 inflammatory
cytokines in the media and adventitia of aneurysmatic vessels
(53). Under certain conditions, activated inflammatory
macrophages express IDO and actively deplete their own Trp
supply. In human macrophages and microglia cells, IFN-g
enhances the expression and activity of KMO (50,54). A
robust increase in KMO expression is associated with high
levels of TNF-aand IL-6 following a systemic inflammatory
challenge (55).
Moreover, accumulating evidence indicates that DCs can also
induce tolerance, rather than immune activation, to the antigens
they present. Similar to promoting immunity, promoting
tolerance requires integrating information that DCs gather
from the innate and adaptive immune systems. Plasmacytoid
dendritic cells (pDCs) can produce type I interferons, such as
IFNaand IFNb, to promote proinflammatory responses by
activating effector T cell, cytotoxic T cells, and NK cells and
can further facilitate AAA development (52,56,57). Dendritic
cells (DCs) respond actively to tolerogenic signals, such as
transforming growth factor-b(TGF-b), which regulates Trp
metabolism. Staining of the aneurysm aortas with a marker of
activated DCs, CD83, showed rare CD83 cells located at the
adventitial/medial border, whereas those cells were not found in
control aortas (58). DCs have been shown to mediate
immunoregulation contributed by Trp catabolism. A study
conducted by Braidy et al. demonstrated the KP activation in
human monocyte-derived DCs (MDDCs) compared to the
human primary macrophages using mRNA expression assays,
high-performance liquid chromatography, mass spectrometry,
and immunocytochemistry. Following activation of the KP using
IFNg, MDDCs can mediate apoptosis of Th cells in vitro (59).
KAT, kynurenine 3‐hydroxylase, and 3‐hydroxyanthranilic acid
dioxygenase (HAAO) appeared to be constitutively expressed in
murine macrophages. Whereas the kynurenine 3‐hydroxylase
andKynuactivityaloneneedIFN‐gstimulation for their
expression (60). IDO1 has been suggested to play a protective
role in atherosclerosis due to its potential immunomodulatory
effect (61). IDO1 is expressed in human atherosclerosis where it
co-localizes with macrophages (46). In the murine systems, the
absence of IDO1 shown to protect against atherosclerosis. Thus,
Metghalchi et al. addressed the direct role of IDO1 in the
modulation of immuno-inflammatory responses and its
potential impact on the development of atherosclerosis. They
also showed IDO1 expression co-localized with macrophages
and SMCs in the aortic sinus of low-density lipoprotein receptor
knock out (Ldlr
−/−
)mice (62). On the other hand, high fat diet
(HFD) dramatically increases IDO activity in macrophages and
VSMC of aortic sinus and circulating levels of KA and QA in
atherosclerosis-prone Ldlr
−/−
mice compared with the chow diet.
A marginal increase of transcriptional expression of IDO1 and
increased protein levels were observed in peritoneal
macrophages after the LPS challenge (63). These results
indicate that Kyn and 3-HAA produced by macrophages are
independently associated with vascular inflammation, suggesting
a connection between macrophage produced Kynu and
arterial remodeling.
Peripheral blood of aortic dissection patients showed a
significant reduction in total lymphocytes, T lymphocytes, and
T helper fractions, with a substantial increase in neutrophils (64)
that shows neutrophils must have a critical role in aortic
pathogenesis. During the AAA progression period, initially
neutrophils stimulate a network of immune cell types that
together can direct a chronic pathological response (65).
Activated neutrophils form neutrophil extracellular traps
(NETs), propagating the inflammatory reactions and
culminating in eventual AAA (56). Neutrophils are also known
to secrete ECM-degrading collagenases such as MMP-8 and
certain proteases (66). In angiotensin II-lysyl oxidase inhibitor
(b-Aminopropionitrile monofumarate; BAPN)–preconditioned
aortic dissection model mice, adventitial neutrophil recruitment
and activation were detected. Furthermore, it was confirmed that
neutrophil-derived IL-6 enhances the adventitial inflammation,
leading to aortic rupture (67). Besides, kynurenines such as
3HAA and 3HK are toxic and can trigger apoptosis in certain
cell types (37,38). Thus, it could be possible that immune
infiltrates are present in the aortas of patients with medial
degeneration could contribute to the local expression of death-
promoting mediators in the diseased aortas. Accumulating data
also shows that these MMPs secretion in the AAA wall (68) are
controlled by inflammatory kynurenines (37,38). MMPs were
thought to be secreted essentially by only mesenchymal and
monocyte/macrophage lineages. However, the neutrophil has
now been recognized as a significant cell type that secretes
these enzymes (67). Neutrophils are thus the vital source of
MMP-2 and MMP-9, two matrix-degrading enzymes known to
be critical in the formation of AAA by regulating KP metabolism.
KP in Vascular Cells and Its Impact in
Aortic Diseases
In many ways, endothelial and smooth muscle cell functions are
linked to the health of the aorta (69). The widespread
mechanisms link endothelial functions and aortic phenotypes
are metalloproteinases and collagenase activation, collagen
production and lysis, median and adventitial degradation,
elastin lysis, and hypertension (70). In addition, endothelial
cells respond to several stimulating factors, including smoking,
hypertension and AT1 receptor stimulation and non-uniform
distribution of the aortic wall (70). Besides, vascular smooth cells
transformation and apoptosis also play a critical role in
determining aortic health. The elaboration of cytokines, such
as IL-2, IFNg, and TNFaby a predominantly Th1 mononuclear
response, stimulates proinflammatory osteopontin secretion
Ramprasath et al. Tryptophan Metabolism Links Aortic Diseases
Frontiers in Immunology | www.frontiersin.org September 2021 | Volume 12 | Article 7317015
from macrophages and vascular smooth muscle cells that further
propagate the inflammatory response (15). Thus, the vascular
phenotype majorly determined by the function and
transformation of vascular cells. Despite the very first product
of the kynurenine pathway, Kyn is a potential contributor to
vessel relaxation; the other products are being studied for their
involvement in vascular pathogenesis. Notable reports from our
lab demonstrated the participation of kynurenine metabolism on
endothelial dysfunction and aneurysm (37,38)(Table 1).
Endothelial dysfunction and endothelial apoptosis are
important factors in many aortic diseases’pathogenesis
including aortic aneurysm. Our group demonstrated the
vasoactive peptide Ang II to induce vascular contractility, EC
apoptosis, and dysfunction by mediating the activation of
oxidative stress. We found that Trp catabolite, 3-HK mediates
Ang II-induced EC apoptosis and subsequently endothelial
dysfunction via the activation of NOX-derived superoxide
anions in vivo. We further demonstrated that Ido1 silencing
could block the effect of Ang II action on endothelium, resulting
in normal endothelial function (38). Wang et al., showed that the
metabolism of tryptophan to kynurenine by IDO expressed in
endothelial cells contributes to arterial vessel relaxation and
blood pressure control (45). Sepiapterin reductase (SPR),
which is one of the crucial enzymes involves in the de novo
synthesis of tetrahydrobiopterin (BH
4
)(42). This BH
4
acts as a
critical regulator of endothelial nitric oxide synthase (eNOS)
function and suggests that BH
4
is a rational therapeutic target in
vascular disease states, particularly for hypertension (71). Several
findings confirmed a causal link between eNOS uncoupling and
BH
4
deficiency in AAA formation (72–74). SPR activity was
reported to be inhibited by XA one of the KP metabolites (43),
which indicates that elevated XA arising out of upregulated KP
could attenuate BH
4
biosynthesis and consequently EC
dysfunction. On the other hand, reduced bioavailability of the
BH
4
also leads to dysregulated eNOS that could increase
superoxide (O−
2) production, which reacts with nitric oxide
(NO) to generate peroxynitrite (75). Peroxynitrite consequently
can nitrate IDO at Tyr15, Tyr345, and Tyr353, and inactivates
IDO (76), which further leads to reduced production
of kynurenine.
Some important cytokines like, IFNg, usually show elevated
level either in Ang II-treated mice or AAA patients (74). Studies
from our group demonstrated a detrimental role of Kynu
produced 3HAA in the pathogenesis of AAA in an AngII-
Apoe
-/-
animal model. Intra-peritoneal injections of 3-HAA for
6 weeks increased the expression and activity of MMP2 in aortas
without affecting metabolic parameters. The acute infusion of
AngII markedly increased the incidence of AAA in Apoe
−/−
mice, but not in Apoe
−/−
IDO
−/−
mice, which presented decreased
elastic lamina degradation and aortic expansion. Findings from
another group also showed an enhanced survival of VSMC when
Ido1 is silenced in murine model systems fed with HFD and
either after infusion of AngII (dissecting AAA) or after topical
peri-aortic elastase (non-dissecting AAA) (77). Mechanistically,
3HAA exposure in SMC mediates the NF-kB activation and
further instigates the MMP2 upregulation (Figure 2). Hence,
IDO1 deficiency can mitigate MMP2 upregulation in AAA
model mice.
AAA is also an age-associated disease and the Trp pathway
alters during aging (78,79). Upregulation of KP in aging is due to
IDO activation by age-related chronic inflammation (22). One
key upstream mechanism that appears to target several pathways
FIGURE 2 | Kynurenines association to vascular diseases. Immune cells under challenged conditions release various cytokines (IFNg, TGF-b, etc.) to regulate the
activation and expression of the kynurenine pathway. Depends on the cell types and milieu, the activated KP effects differently. For example, in SMCs, 3-HAA
triggers NF-kB and MMPs, which further degrades ECM. In endothelial cells, tryptophan catabolite 3-HK activates the NOX and produces superoxide. This
superoxide further shoots up the apoptotic signaling. Trp, tryptophan; 3-HAA, 3-hydroxyanthranilic acid; AngII, angiotensin II; ECM, extracellular matrix; NOX,
NADPH oxidase. 3-HK-3-hydroxykynurenine.
Ramprasath et al. Tryptophan Metabolism Links Aortic Diseases
Frontiers in Immunology | www.frontiersin.org September 2021 | Volume 12 | Article 7317016
with age is kynurenine, a tryptophan metabolite and an
endogenous aryl hydrocarbon receptor (AhR) agonist. The
AhR signaling pathway has been reported to promote aging
phenotypes across species and in different tissues (78,80). Thus,
mitigation of target receptors could prevent the kynurenine-
induced increase in senescence-associated b-galactosidase and
p21 levels and block aggregation of nuclear H3K9me3 (Histone 3
lysine 9 trimethylation) (79). Cellular senescence has historically
been viewed as an irreversible cell-cycle arrest mechanism with
complex biological processes such as development, tissue repair,
ageing, and age-related disorders like aortic aneurysms. Thus, it
is well understood that kynurenine metabolism involves
triggering the senescence of vascular cells and targeting and
controlling the activation of tryptophan metabolism may limit
the development of AAA. Overall, casual relationships were well
established between Kyn pathway and the development of AAA.
Clinically, determining the Kyn or 3-HAA level at early stages in
human patients could suggest that tryptophan-derived
metabolites could be used as an early biomarker to identify
AAA and atherosclerosis.
As reported above, many of these inflammatory signaling
proteins are essential for cell cycle regulation. Hence,
considerable enthusiasm remains for further investigations in
thisarea,aswellasitisyettostudyusingtheKP
pharmacological modulators for these KP enzyme proteins.
Hence, it might be worth exploring the possible impact of
modulating KP, which are regulated by cytokines for treating
aortic diseases.
TARGETING KP AS A THERAPEUTIC
TARGET FOR AORTIC DISEASES
Despite, there is no clinical trial was carried out with KP
inhibitors to target the vascular diseases, KP activation has
been observed in inflammation-related vascular diseases, such
as atherosclerosis, AAA, and endothelial dysfunction. Many of
the available KP inhibitors are known to inhibit inflammation
during in vivo experiments. For example, in vivo experiments
using animals have demonstrated that targeting IDO1, KMO,
KYNU, and KAT II KP enzymes can regress cardiovascular
diseases by reducing inflammation (22). Hence, pharmacological
manipulation of the KP enzymes employing the drugs based on
structures becomes an attractive drug development area. Thus,
we may expect the emergence of kynurenines enzyme based
modulators in future. In the following sections, we briefly outline
some KP modulators tested at pre-clinical and clinical levels.
IDO1 and TDO Inhibition and Its Effect on
Reducing Inflammation
A well-known IDO1 inhibitor used clinically is 1-MT (referred to
as Indoximod), the first and widely used competitive inhibitor of
IDO1. Other notable IDO1 inhibitors are INCB024360 and
NLG919 (an imidazoleisoindole derivative). NLG919 a potent
direct small molecule IDO1 inhibitor, was tested in clinical trials
(81). In another study, navoximod (GDC-0919, NLG-919)
intervention in patients with tumor showed transiently
decreased plasma kynurenine from baseline levels with kinetics
consistent with its half-life (82,83). TDO is also actively being
tested to use as a target for cancer (84). The indole structure (3-
(2-(pyridyl)ethenyl)indoles) based TDO inhibitor had proven
pharmacokinetic profile and was tested for preclinical evaluation
in cancer patients (85). However, it should be taken into
consideration that systemic TDO inhibition will result in
increased levels of TRP metabolites such as KYN due to
increased availability of TRP for IDO1 as observed in the
TDO-deficient mice (84). Depends on the environment and
cell types Ido1 deficiency as well as IDO1 inhibition, is known
to enhance the atherogenesis. However, the IDO1 inhibitor
epacadostat has contrasting effect s on macr op hages, wh ich
could reduce the tissue factor (TF). IDO1 expressed in
coronary atherosclerotic plaques was reported to contribute to
FIGURE 3 | Important KP enzymes and their Inhibitors. Figure explains some KP modulators tested at pre-clinical and clinical levels. Refer to the text for the
expanded form of abbreviations.
Ramprasath et al. Tryptophan Metabolism Links Aortic Diseases
Frontiers in Immunology | www.frontiersin.org September 2021 | Volume 12 | Article 7317017
thrombus formation by upregulated expression of TF in
activated macrophages. The IDO1 inhibition by epacadostat,
significantly reduced the TF expression by reducing the Kyn/Trp
ratio and activity, as well as NF-kB (p65) binding activity in
activated macrophages. Further, epacadostat could inhibit the
aryl hydrocarbon receptor (or binding of Kyn to AhR) and
reduced Kyn-induced TF expression in activated macrophages
(25). In another way, the inhibition of AHR by its specific
inhibitor CH223191 also significantly inhibited Kyn-induced TF
expression in activated macrophages (25)(Figure 3). Besides,
recent research also indicates that 1-MT induces an increase
of KYNA in ex vivo and in vivo. Consistently, IDO
−/−
mice also
showed an increase of KYNA as Ido1 deficiency promotes a
shift toward this branch of the kynurenine pathway (KP),
which may be one potential mode of action by 1-MT and
should be considered for further applications (86). These
findings collectively suggest that the IDO1-mediated Kyn
pathway plays a significant role in aortic diseases, and this area
needs more study to decide pharmacological modulation of Ido1
and TDO enzyme activities to cure vascular inflammation
associated diseases.
Other KP Enzyme Inhibition for Reducing
Vascular Inflammation
KMO expression was shown to be upregulated in response to
challenging inflammatory conditions (55). Hence, KMO
inhibition has been recognized as a potential therapeutic strategy
to ameliorate inflammatory diseasesin several animal models (87–
89). From a therapeutic point of view, KMO is located at a critical
branching point in the KP, its activity mediating opposite effects in
the levels of 3-HK and QA versus KYNA.
KMO inhibitors based on the structure of the natural
substrate KYN is m-Nitrobenzoylalanine (m-NBA), has an
IC50 of 0.9 mMagainstKMO(90). Intraperitoneal
administration (400 mg/kg) of this compound in rodents
decreased the levels of 3-HK while increasing the levels of
KYNA. Thus, inhibition of KMO should shunt the pathway
away from the toxic metabolites 3-HK and QA and toward the
formation of the protective metabolite KYNA (91). KYNA was
assumed to have role as anti-inflammatory. KYNA decreased
phosphorylation of extracellular signal-regulated kinases (ERK)
1/2, p38 MAPK, and Akt in colon epithelial cells. Further, it was
also found to induce the accumulation of b-catenin. MAPK,
PI3K/Akt and b-catenin pathways are well-known targets of
GPR signaling (87,88)(Figure 3). Therefore, it is possible that
the observed inhibition of ERK and p38 and the induction of b-
catenin accumulation after KYNA treatment are a consequence
of GRP35 activation. Interestingly, all of these described effects of
KYNA–GPR35 signaling might lead to the suppression or
limitation of inflammation (92). Thus, inhibition of KMO can
shunt the pathway away from the toxic metabolites 3-HK and
QA and toward the formation of the protective metabolite
KYNA. Similarly, many other KP enzyme inhibitors including,
KMO inhibitors (GSK180, Ro-61-8048, UPF-648), KYNU
inhibitors (o-Methoxybenzoyalanine, S-phenyl-L-cysteine
sulfoxide), KAT inhibitors (PF-04859989, BFF 122) were also
tested for their efficiency to reduce inflammatory diseases (22). In
addition, Swainson et al. found that KMO inhibition using
CHDI-340246 decreased acute simian immunodeficiency virus
infection-induced increases in plasma levels of cytotoxic 3-HK
and QA, and improved clinical outcomes as indicated by
increased CD4+ T cell count and body weight (93). Despite
this, the role of KMO inhibition in CVD is still unclear. Recently,
Masanori Nishimura et al. found that both gene and protein
expression levels of KMO were upregulated in macrophages in
atherosclerotic aneurysmal samples obtained from patients (94).
In another experiment, oxazolidinone GSK180 (3-(5,6-dichloro-
2-oxobenzo[d]oxa-zol-3(2 H)-yl)propanoic acid; a KMO
inhibitor), was shown to prevent extrapancreatic tissue injury
to the many organs (88). However, further in vivo experiments
using KMO inhibitor or knockout animals will help clarify the
effects and potential mechanism of KMO in aortic aneurysms
and related aortic diseases.
It was shown that 3-HAA, can modulate vascular
inflammation and lipid metabolism. Supplementation of 3HAA
reduced the athero formation (44) and blocking of HAAO (that
catabolize 3HAA into other derivatives) by NCR-631 increased
endogenous levels of 3-HAA, which reduced atherosclerosis
(47)(Figure 3). Though many of these inhibitors were
validated pre-clinically, their efficiency of inhibition of KP
enzymes for vascular diseases and their application in the
vascular field is largely unexplored. Understanding the
outcome of multiple levels of KP inhibition would help us
identify a potential target that would provide us with a choice
to cure aortic diseases.
CONCLUSIONS AND CLINICAL
PERSPECTIVES
As per our current knowledge, in the United States, out of >200 000
new patients diagnosed for AAA, >40000 patients are undergoing
highly morbid aortic reconstructions. This approach is a
catastrophic event associated with near-certain mortality, and no
pharmaceutical currently exists to slow aneurysm growth (95).
Evidence shows that targeting inflammation in vascular diseases
could reduce secondary cardiovascular events (96).
Evidence-based studies confirmed the perturbed tryptophan
metabolism and its association with many aortic diseases,
particularly atherosclerosis and AAA. AAA most likely
associated to the perturbed cytokine levels, which is linked to
the disturbed tryptophan metabolism. Cytokines lead generation
of kynurenines in immune or vascular cells, further triggers
vascular inflammation. This metabolic behavior shows many
commonalities to share with other vascular immune disorders.
Generally, chronic inflammation drives initial aortic ectasia and
dilation, and later, the tension on the aortic wall continues to
expand. When wall tension drives sac expansion, no medical
intervention will work except surgical aortic reconstruction (95).
Hence, we may assume that limiting the inflammation-mediated
downstream mechanisms, particularly the kynurenine pathway,
emphasizes a further trend and application of these interventions.
Ramprasath et al. Tryptophan Metabolism Links Aortic Diseases
Frontiers in Immunology | www.frontiersin.org September 2021 | Volume 12 | Article 7317018
Furthermore, as the product to substrate ratio of tryptophan
metabolism is an indicator of vascular inflammation, controlling
the patients’Trp metabolic profile could be viable if anyone is
diagnosed earlier. This will also allow early identification of
patients at risk of vascular diseases that could be crucial to the
success of nonsurgical treatment.
AUTHOR CONTRIBUTIONS
TR: Conceived idea and wrote the manuscript. Y-MH, DZ, and
C-JY: Revised the manuscript. M-HZ: Conceived idea and
revised the manuscript. All authors contributed to the article
and approved the submitted version.
FUNDING
This work was supported by the AHA postdoctoral fellowship
award: 19POST34380156 to TR. M-HZ is a recipient of the
National Established Investigator Award of the American
Heart Association.
ACKNOWLEDGMENTS
We thank Dr. Ping Song M.Sc., PhD, for his critical review and
comments to improve the manuscript.
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