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Cerven Ka 2017
Cerven Ka 2017
Cerven Ka 2017
The kynurenine pathway generates tryptophan metabolites with profound. They serve as important mediators of interorgan and
diverse biological activities throughout the body. Although mainly interkingdom cross-talk, connecting seemingly diverse processes
studied in relation to the brain and mental health, the action of such as the effects of exercise training and pathologies such as
kynurenine metabolites on peripheral tissues might be even more inflammatory diseases, cancer, and depression.
T
peroxisome proliferator–activated receptor (PPAR)
ryptophan (Trp) is an essential amino acid the CNS is divided between different cell types, gamma coactivator-1a1 (PGC-1a1), which enhances
critical for protein synthesis, but it also serves among which astrocytes and microglia play impor- KAT gene expression and Kyn to Kyna conversion.
as substrate for the generation of several bio- tant roles with antagonizing actions (6). Microglia This links peripheral and central Kyn metabolism
active compounds with important physiolog- produce quinolinic acid (Quin), an N-methyl-D- and provides a mechanism for some of the benefits
ical roles. Probably the best-known fate of Trp aspartate receptor (NMDAR) agonist, whereas as- of physical exercise for mental health.
is its conversion to serotonin (5-hydroxytryptamine), trocytes are equipped to generate kynurenic acid
an important neurotransmitter involved in the con- (Kyna), an NMDAR and a7 nicotinic acetylcholine The many fates of tryptophan
trol of adaptive responses in the central nervous receptor (a7nAChR) antagonist. The levels of these Humans lack the biochemical pathways to synthe-
system (CNS) and linked to alterations in mood, two Kyn metabolites have hence been associated size Trp, which must be acquired from diet with a
anxiety, or cognition (1). Serotonin can be further with neuronal excitotoxicity (Quin) or protection required daily dose of 3.5 mg per kg of weight (23).
converted to N-acetylserotonin (NAS) and mela- (Kyna) and are found to be dysregulated in major The highest concentration of Trp can be found in
tonin, adding control over circadian rhythmicity depressive disorders and schizophrenia (7). chocolate, eggs, fish, dairy products, legumes, and
to the list of biological roles for Trp metabolites Like Trp and Kyn, 3-hydroxykynurenine (3-HK) meat. Less than 1% of ingested Trp is used for
(2). However, in mammals, the majority of free crosses the BBB and contributes to Quin gener- protein synthesis because, under conditions of un-
Trp is degraded through the kynurenine pathway ation in microglia but is also able to exert more altered nitrogen balance, the demand for protein
(KP) (Fig. 1) and generates a range of metabolites direct deleterious effects linked to oxidative stress synthesis is met by protein breakdown (24). The
involved in inflammation, immune response, and and apoptosis (8, 9). Defects in Kyn signaling have majority of Trp is thus metabolized along one of
excitatory neurotransmission (3). The final prod- also been seen in mouse models of neurodegenera- four known pathways, giving rise to a variety of
uct of the KP is nicotinamide adenine dinucleotide tive diseases such as Alzheimer’s and Huntington’s biologically active compounds (e.g., serotonin, trypt-
(NAD+), an important cofactor in cellular reactions (10, 11). The underlying feature of these different amine, indoles, kynurenines, and NAD+) (25). Trp,
linked to energy metabolism (4) that is emerging pathologies seem to converge on neuroinflamma- together with other neutral amino acids, is trans-
as an attractive therapeutic target for several dis- tion and associated events, including brain infiltra- ported by large neutral amino acid transporters
eases. Here, we focus on peripheral mechanisms tion of circulating immune cells, microglia activation, (LAT) 1 to 4. These are widely distributed through-
that contribute to Trp-KP metabolism. and high levels of proinflammatory cytokines (12). out the body, and their capacity is sufficient to
Kynurenine (Kyn) and its metabolites (all with The levels of enzymes of the KP in peripheral avoid competition, with the notable exception
defined chemical identities but often collectively tissues tend to be much higher than in the brain. of the BBB (26). The majority of Trp is imported
called “kynurenines”) are known for their effects For example, macrophages have a 20-fold higher into the gut, where only a fraction is used, whereas
on the CNS and have been linked to several psy- capacity to produce Quin than microglial cells. This the rest enters portal circulation and undergoes
chiatric and mental health disorders such as de- is particularly important in situations of macro- liver metabolism. The remaining Trp, together
pression and schizophrenia (5). The CNS receives phage infiltration across the BBB. Immune cells with its liver degradation products, is distributed
about 60% of Kyn from the periphery by transport are both important sources and targets for Kyn to peripheral circulation and transported to tissues
across the blood-brain barrier (BBB), and the re- metabolites as they express high levels of several such as the brain, heart, and skeletal muscle. Trp
maining is produced locally. Kyn degradation in enzymes of the pathway [e.g., indoleamine 2,3- not taken up by the upper GIT is metabolized by
dioxygenase (IDO) and kynurenine aminotrans- resident microbiota to indole compounds (27), im-
ferases (KATs)] and also of receptors such as G portant interspecies signaling molecules (28).
Department of Physiology and Pharmacology, Molecular and
Cellular Exercise Physiology, Karolinska Institutet, SE-17177
protein–coupled receptor 35 (GPR35). The expres- Trp is the only amino acid transported bound
Stockholm, Sweden. sion of IDO and KATs allow Trp to be metabo- to albumin. However, degradation pathways can
*Corresponding author. Email: jorge.ruas@ki.se lized to Kyna, a GPR35 agonist (13) and a ligand only use Trp in its free form, which corresponds
to 5 to 10% of total Trp (29). The mode of Trp under the control of two IDO enzymes (IDO1 and These ratios change dramatically under different
degradation and concentration of its end products the more recently discovered IDO2), whose activity Trp loads and are also influenced by vitamin B6
is a function of free Trp concentration, which is in is negligible under basal conditions but dramat- availability (45). Our understanding of how the
turn readily influenced by nutritional, hormonal, ically inducible by several stimuli, such as inflam- proportions of different Kyn metabolites change
and pharmacological cues. For example, nones- matory signals (e.g., interferon-g). IDOs are mostly with environmental context is incomplete, and
terified fatty acids (NEFA) directly affect Trp avail- active in the immune system and mucosal tissues many contradictory results have been reported.
ability by displacing it from albumin (30). As a such as gut (38, 39). Conversely, IDO can be inhi- Interestingly, this has prompted the development
consequence, increasing NEFA levels by, for ex- bited by elevated levels of Trp, which results in of mathematical models to help us understand
ample, adrenaline or phosphodiesterase inhib- channeling the flux of Trp degradation back to metabolite flux through the KP (46).
itors, increases free Trp. Conversely, antilipolytic TDO (40). Interestingly, the TDO and IDO genes
agents such as insulin are able to decrease Trp do not share a common ancestor but are an ex- Conservation of kynurenine metabolism
concentration by the same mechanism (25). ample of functional convergence (41). throughout evolution
The gut microbiota numbers are estimated to The KP can yield metabolites with neurotoxic In bacteria, fungi, and plants, the biosynthesis of
outnumber cells in our body by a factor of 10 and and neuroprotective properties, depending on aromatic amino acids such as Trp is provided by
tend to increase distally along the intestine (31). which enzyme tips the conversion scales (5). Under the shikimate pathway. Whereas bacteria spend
Due to their sheer number, they have nonnegligible normal conditions, the majority of Kyn is excreted the majority of their metabolic energy on protein
effects on Trp metabolism. Gut microbiota can in the urine, so its bioavailability only increases synthesis, plants use this pathway to generate a
directly absorb Trp and thus limit its availability when the flux of Trp down the KP exceeds renal large variety of secondary metabolites (47). Regard-
to the host organism. This can be seen in germ- clearance (42). Kyn is usually hydroxylated to 3-HK ing the conservation of the KP, the TDO enzyme
free (GF) mice, which have high circulating Trp and then further converted to 3-hydroxyanthranilic can be found in the majority of bacterial species and
levels that normalize postcolonization. Bacterially acid (3-HAA). 3-HAA is rapidly converted to Quin in almost all metazoan species but has probably
produced indoles interact with pregnane X recep- by the nonenzymatic reaction of an intermediary been lost in fungi during the course of evolution
The highest concentrations are found in honeybee (13, 74). Of those, circulating monocytes display
products, broccoli, and some potatoes (50). Many the highest expression of GPR35, and its interac-
medicinal herbs contain high concentrations of tion with Kyna has been shown to promote mono-
Kyna, indicating therapeutic potential for the gas- cyte extravasation (75). It was later confirmed that
trointestinal system (51). In addition to the Kyna Kyna-GPR35 interaction reduces the inflamma-
ingested in food or synthesized along the KP in tory response induced by lipopolysaccharide (LPS)
the GIT, the gut microflora possesses the enzyme stimulation in monocytes and macrophages (76)
aspartate aminotransferase, which is analogous to and controls cytokine release in human iNKT cells
mitochondrial KAT4 and produces Kyna by trans- (74). Taken together, the effects of Kyna on im-
amination of Kyn. The action of Kyna on the GIT mune cell activation might represent a direct anti-
is several fold. Early reports suggested that Kyna inflammatory mechanism that further reinforces
is able to protect the intestinal mucosa in the settings the immunosuppressant function of Trp catabo-
of obstructive jaundice and protect from ethanol- or lism. Other metabolites of the KP, such as 3-HAA
toxin-induced ulcers (52). In addition, Kyna can also and Quin, have been shown to induce apoptosis
modulate local inflammation, most likely through of type 1 T helper (TH1) cells, while promoting pro-
activation of GPR35, which is highly expressed in liferation of type 2 T helper (TH2) cells (67). This
the immune cells of the GIT. immune shift would favor cell survival against the
Fig. 2. Evolutionary conservation of enzymes deleterious effect of uncontrolled immune activation.
Liver control of tryptophan-kynurenine of the kynurenine pathway. KYNU, Inflammatory conditions are characterized by
metabolism Kynureninase. high levels of cellular stress and energy use, often
Among the many cell types that express KP enzymes, accompanied by increased rates of DNA damage.
hepatocytes contain all the machinery required Trp catabolism in the host microenvironment In macrophages, as in the liver, oxidation of Trp
during physical exercise, skeletal muscle can oxidize production and signaling in enterochromaffin enines with AhR and their actions on the immune
branched-chain amino acids (BCAA) and Trp for cells (87, 88). One of the hallmarks of the disease, system (93).
energy (81). Muscle fibers contain all the neces- visceral hypersensitivity, is thought to occur as a
sary transporters/carriers for amino acid clearance; result of the sensitization of afferent neurons and Pancreatitis
however, circulating BCAA compete with Trp and to compromised epithelial integrity, which in turn One of the less-studied diseases with connection
kynurenines for the same transporters (82). More- makes it possible for intraluminal compounds to to Trp metabolism is acute pancreatitis (AP). It
over, BCAA inhibit some of the enzymes of the cross the gut wall barrier (89). is a severe sterile inflammation of the pancreas
KP (83), especially KATs (84), which indicates By contrast, IBD is a relapsing inflammatory connected to gut dysfunction that can lead to
that fuel availability (in particular, BCAA) can condition with complex etiology that affects 1 in multiorgan failure with very high mortality rates
affect skeletal muscle Trp metabolism and Kyn 500 individuals, peaking around the age of 20. (94). Plasma Kyn of AP patients seems to originate
clearance. The etiology of IBD lies at the intersection of in the gut-associated lymphoid tissue (GALT), and
dysbiosis of microbiota, host immunity, and genetic its levels correlate with magnitude of injury and
Kynurenine metabolites and disease predisposition, with anxiety and depression as systemic inflammatory burden (95). Kynurenine-
Trp metabolism is most widely known and studied common comorbidities (90). In this context, it is 3-monooxidase (KMO) is central to the patho-
in relation to disorders of the nervous system. Its not unexpected that aberrant Trp metabolism is genesis of pancreatitis, and its genetic ablation
effect on stress-related depression, schizophrenia, a common denominator of these complications. or pharmacological inhibition conveys protection
and Alzheimer’s and Parkinson’s diseases have IBD patients have increased plasma levels of Kyn from deleterious effects. The pathology of AP is
been comprehensively reviewed elsewhere (85). and Kyna, probably as a result of increased IDO mediated by 3-HK transported in the mesenteric
The following sections summarize recent advances expression. IBD is also connected to microbiota lymph to other organs such as the lungs, where it
in our understanding of how Kyn metabolism homeostasis, and IBD patients also have increased causes near total cell death by oxidative stress,
is dysregulated in peripheral tissue dysfunction. risk of colorectal cancer (91). Recently, caspase apoptosis, and pathological protein cross-linking
However, it is important to remember that the recruitment domain–containing protein 9 (CARD9) (96). Decreasing 3-HK production from Kyn by
majority of defects of Trp metabolism in peripheral has been found to be an IBD susceptibility gene. diverting it to generating Kyna inhibits LPS-induced
organs can also have a strong effect on the CNS, CARD9 encodes a host adaptor protein critical TNFa secretion and leads to increased survival
resulting in complications such as anxiety and for immune responses against microorganisms. in rodent models of acute pancreatitis (96). Melatonin,
depression. Microbiota derived from CARD9 knockout (KO) another Trp metabolite, has emerged as a treat-
mice have compromised Trp to indole conversion ment option of AP by reducing oxidative stress
Irritable bowel syndrome and disease and cannot activate AhR. Furthermore, bacteria and protecting from inflammation (97).
Two main diseases of the GIT are associated with from CARD9 KO animals are sufficient to induce
Trp metabolism: irritable bowel syndrome (IBS) colitis in wild-type germ-free animals. Coloniza- Cancer
and irritable bowel disease (IBD). IBS is charac- tion of CARD9 KO animals with bacteria capable Cancer cells have a multifaceted relationship with
terized by abdominal pain together with altered of catabolizing Trp alleviates the disease (92). Due altered Trp metabolism. Several tumor types show
bowel habits and affects a considerable portion to the tight regulation between microbiota and increased Trp uptake [as evidenced by a-[11C]-
of the adult population (15 to 20%) (86). Increase host responses, individual contributions will prove methyl-L-tryptophan (AMT)–positron emission
in serum-free Trp has been documented in IBS challenging to distinguish. Interestingly, plant- tomography (PET) scanning of human patients],
patients. The etiology of IBS has been connected derived indole compounds have been used in tra- which in turn correlates with poor disease prog-
to abnormal serotonergic neuronal signaling during ditional medicine to treat IBD, which lends support nosis (98). Although the reason for this is not fully
development and also to alterations in serotonin to the importance of the interactions of kynur- understood, tumor cells might need high Trp levels
to fuel an ever-increasing demand for protein elevates the synthesis of serotonin in the liver and Trp degradation pathways and the concentra-
synthesis. On the other hand, Trp starvation will adipose tissue in a tryptophan hydroxylase 1 (Tph1)– tion of their biologically active products has not
induce general control nonderepressible 2 (GCN2) dependent manner. Serotonin binds to mecha- been investigated.
kinase that inhibits G1 to S transition, inducing nistic target of rapamycin (mTOR), increasing During the course of many of the aforemen-
cell cycle arrest (99). To prevent this, tumors might liver lipogenesis and impairing insulin signaling tioned diseases and in the process of aging, the
increase their Trp supply by up-regulating LAT1 in adipocytes. Accordingly, inhibition of serotonin intracellular levels of Trp and NAD+ can fall if
expression. However, LAT1 has been shown to degradation by monoamine oxidase A (MAOA) the KP is stressed by inflammation or imbalance
work in a bidirectional manner, exchanging gluta- exacerbates the effects (110). Compounding the between catabolic and anabolic substrates. How-
mate for Trp. To counteract this shortcoming, it problem, serotonin has well-documented effects ever, de novo synthesis from Trp is not a very
has been shown that proliferating tumor cells, on brain-mediated control of appetite. Despite its efficient way to boost NAD+ levels, because it
but not resting T cells, up-regulate expression of anorexigenic effects, serotonin transporter (SERT) requires very high Trp to saturate other branches
the glutamate transporter by the activating tran- KO animals are obese and, conversely, Tph1 and of the catabolic pathway (4). Nevertheless, NAD+
scription factor 4 (ATF4) pathway after sensing 2 KO mice lose body weight (111). Several studies boosting strategies seem to be successful in re-
Trp unavailability (100, 101). Moreover, tumors have highlighted the role of serotonin in the regu- storing mitochondrial and stem cell function (121)
show enhanced IDO expression, with downstream lation of white and brown adipose tissue energy and in ameliorating diseases such as muscular
metabolites, such as Kyn, being able to activate storage and expenditure. Serotonin can increase dystrophy and diabetes (122, 123) or even pro-
beta-catenin signaling, leading to increased colon fat accumulation in humans and rodents, and longing life span (124). Our understanding of age-
cancer proliferation in mice (102). IDO expression the activation of its receptors in hypertrophied related effects of the KP is still largely incomplete.
in mouse models of ovarian cancer, melanoma, fat cells induces adiponectin production. Con- However, there is a general notion that altera-
and renal cell carcinoma correlates with increased versely, Tph1 KO mice have significantly lower tions of the KP can bring about oxidative stress,
angiogenesis (103). TDO, on the other hand, has weight, improved glycemic control, enhanced immune response decline, or inflammation. Lower
been predominantly connected to the escape from energy expenditure, and lower adiposity when levels of Trp and TDO activity have been reported
in patients, facilitating microbe invasion leading their biological activity. While exploring their 11. W. Wu et al., Expression of tryptophan 2,3-dioxygenase and
to potentiated systemic immune activation (131). role in the brain and processes affecting mental production of kynurenine pathway metabolites in triple
transgenic mice and human Alzheimer’s disease brain.
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