Effects of inflammation on the kynurenine pathway in schizophrenia - a systematic review

Abstract

Background: In the last decade, there has been growing evidence that an interaction exists between inflammation and the kynurenine pathway in schizophrenia. Additionally, many authors found microglial activation in cases of schizophrenia due to inflammatory mechanisms related mostly to an increase of pro-inflammatory cytokines. In order to gain new insights into the pathophysiology of schizophrenia, it is important to incorporate the latest published evidence concerning inflammatory mechanisms and kynurenine metabolism. This systematic review aims to collect reliable recent findings within the last decade supporting such a theory.

Methods: A structured search of electronic databases was conducted for publications between 2008 and 2018 to identify eligible studies investigating patients with schizophrenia/psychosis and the relationship between inflammation and kynurenine pathway. Applicable studies were systematically scored using the NIH Quality Assessment Tools. Two researchers independently extracted data on diagnosis (psychosis/schizophrenia), inflammation, and kynurenine/tryptophan metabolites.

Results: Ten eligible articles were identified where seven studies assessed blood samples and three assessed cerebrospinal fluid in schizophrenic patients. Of these articles: Four investigated the relationship between immunoglobulins and the kynurenine pathway and found correlations between IgA-mediated responses and levels of tryptophan metabolites (i.e., kynurenine pathway).Five examined the correlation between cytokines and kynurenine metabolites where three showed a relationship between elevated IL-6, TNF-α concentrations, and the kynurenine pathway.Only one study discovered correlations between IL-8 and the kynurenine pathway.Two studies showed correlations with lower concentrations of IL-4 and the kynurenine pathway.Moreover, this systematic review did not find a significant correlation between CRP (n = 1 study), IFN-γ (n = 3 studies), and the kynurenine pathway in schizophrenia.

Interpretation: These results emphasize how different inflammatory markers can unbalance the tryptophan/kynurenine pathway in schizophrenia. Several tryptophan/kynurenine pathway metabolites are produced which can, in turn, underlie different psychotic and cognitive symptoms via neurotransmission modulation. However, due to heterogeneity and the shortage of eligible articles, they do not robustly converge to the same findings. Hence, we recommend further studies with larger sample sizes to elucidate the possible interactions between the various markers, their blood vs. CSF ratios, and their correlation with schizophrenia symptoms.

Keywords: Glutamic acid; Inflammation; Kynurenic acid; Kynurenine; Schizophrenia.

Fig. 1

Kynurenine pathway and tryptophan metabolism in the central nervous system. In the central nervous system (CNS), the kynurenine pathway starts by the conversion of tryptophan into kynurenine by indoleamine 2,3-dioxygenase 1 (IDO1), IDO2, or tryptophan 2,3-dioxygenase (TDO). Astrocytes can express both types of enzymes while microglia express only IDO [18, 23]. To a lesser extent, some neurons also possess IDO and/or TDO producing a minor portion of kynurenine [18]. Therefore, kynurenine is available in the CNS via the enzymatic activity of astrocytes, microglia, and some neurons as well as the kynurenine being actively transported into the brain by the large neutral amino acid transporter [19]. Next, kynurenine can follow either of two metabolic branches. First, it can be metabolized into kynurenic acid (KYNA) via kynurenine aminotransferase (KAT) [19, 24, 25] in astrocytes mainly [26] and neurons through irreversible transamination by KAT [27]. The other branch leads to the formation of quinolinic acid (QUIN) exclusively in both microglia and infiltrating macrophages. Both can express kynurenine 3-monooxygenase (KMO) which is absent in human astrocytes [28]. However, both astrocytes and neurons can further catabolize QUIN, produced by neighboring microglial cells, by the enzyme quinolinate phosphoribosyltransferase (QPRTase) [23]. They can also form the neuroprotective picolinic acid (PIC) as they express the enzyme aminocarboxymuconate semialdehyde decarboxylase (ACMSD) [27]. Molecules: 3HAA, 3-hydroxyanthranilic; 3HK, 3-hydroxy-kynurenine; AA, anthranilic acid; ACMS, 2-amino-3-carboxymuconate semialdehyde; KYN, kynurenine; KYNA, kynurenic acid; NAD+, nicotinamide adenine dinucleotide; PIC, picolinic acid; QUIN, quinolinic acid; TRP, tryptophan; XA, xanthurenic acid. Enzymes: 3-HAO, 3-hydroxyanthranlic acid oxygenase; ACMSD, aminocarboxymuconate semialdehyde decarboxylase; IDO, indoleamine 2,3-dioxygenase; KAT, kynurenine aminotransferase; KMO, kynurenine 3-monooxy-genase; KYNU, kynureninase; QPRT, quinolinic acid phosphoribosyltransferase; TDO, tryptophan-2,3-dioxygenase. *Excitation (examples): tryptophan, T-lymphocytes A4, IFN-α, IFN-β, IFN-γ, TNF α. *Inhibition (examples): IL-4, Th2 immunity response, antidepressants, antipsychotics

Fig. 2

PRISMA flow diagram. *Non-original articles comprise literature reviews, systematic reviews, meta-analyses, and conference abstracts. From Moher et al. [39]