Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia

Abstract

The kynurenine pathway (KP) of tryptophan (TRP) catabolism links immune system activation with neurotransmitter signaling. The KP metabolite kynurenic acid (KYNA) is increased in the brains of people with schizophrenia. We tested the extent to which: (1) brain KP enzyme mRNAs, (2) brain KP metabolites, and (3) plasma KP metabolites differed on the basis of elevated cytokines in schizophrenia vs. control groups and the extent to which plasma KP metabolites were associated with cognition and brain volume in patients displaying elevated peripheral cytokines. KP enzyme mRNAs and metabolites were assayed in two independent postmortem brain samples from a total of 71 patients with schizophrenia and 72 controls. Plasma KP metabolites, cognition, and brain volumes were measured in an independent cohort of 96 patients with schizophrenia and 81 healthy controls. Groups were stratified based on elevated vs. normal proinflammatory cytokine mRNA levels. In the prefrontal cortex (PFC), kynurenine (KYN)/TRP ratio, KYNA levels, and mRNA for enzymes, tryptophan dioxygenase (TDO) and kynurenine aminotransferases (KATI/II), were significantly increased in the high cytokine schizophrenia subgroup. KAT mRNAs significantly correlated with mRNA for glial fibrillary acidic protein in patients. In plasma, the high cytokine schizophrenia subgroup displayed an elevated KYN/TRP ratio, which correlated inversely with attention and dorsolateral prefrontal cortex (DLPFC) volume. This study provides further evidence for the role of inflammation in a subgroup of patients with schizophrenia and suggests a molecular mechanism through which inflammation could lead to schizophrenia. Proinflammatory cytokines may elicit conversion of TRP to KYN in the periphery and increase the N-methyl-D-aspartate receptor antagonist KYNA via increased KAT mRNA and possibly more enzyme synthesis activity in brain astrocytes, leading to DLPFC volume loss, and attention impairment in schizophrenia.

Fig. 1

Overview of the kynurenine pathway (KP). TDO tryptophan-2,3-dioxygenase, IDO indoleamine 2,3 dioxygenase, IL-1β interleukin 1 beta, IL-6 interleukin 6, KMO kynurenine 3 monooxygenase, KAT kynurenine amino transferase, GFAP glial fibrillary acidic protein, IBA ionized calcium-binding adaptor molecule, KYNU kynureninase, 3HAO 3-hydroxyanthranilic acid 3,4-dioxygenase

Fig. 2

Inflammatory subgroup differences of kynurenine pathway enzyme mRNA expression in New South Wales Tissue Resource Centre (NSW TRC) and Stanley Medical Research Institute (SMRI) combined postmortem brain tissue. a Tryptophan-2,3-dioxygenase (TDO) mRNA expression was significantly greater in people with schizophrenia who were in the high cytokine subgroup (p = 0.02). b Kynurenine aminotransferase (KAT) I mRNA expression was significantly greater in people with schizophrenia who were in the high cytokine subgroup (p = 0.01) than other groups. c Similarly, KAT II mRNA expression was significantly greater in people with schizophrenia who were in the high cytokine subgroup (p = 0.01) than other groups. d No statistically significant differences in kynurenine 3 monooxygenase (KMO) mRNA expression were detected among groups. *p < 0.05, **p < 0.01, ***p < 0.001

Fig. 3

Correlations of kynurenine aminotransferases I (a, b) and II (c, d) (KATI/II) mRNA expression with glial fibrillary acidic protein (GFAP) in postmortem brain tissue. KATI mRNA expression significantly correlates with GFAP mRNA in a controls (p = 0.001) and b schizophrenia (p = 0.008), whereas a significant correlation for KATII was only found in d schizophrenia patients (p = 0.03)

Fig. 4

Inflammatory subgroup differences of kynurenine (KYN) pathway metabolites in postmortem brain tissue. a KYN/tryptophan ratio was significantly greater in people with schizophrenia who were in the high cytokine subgroup (red, p < 0.001) compared to both low cytokine controls (light blue) and low cytokine schizophrenia (pink) subgroups. b Kynurenic acid (KYNA) was significantly greater in people with schizophrenia who were in the high cytokine subgroup (red) compared to the low cytokine controls (light blue) (p = 0.013). c KYNA/quinolinic acid ratio was significantly greater in people with schizophrenia who were in the high cytokine subgroup (red) as compared to the normal cytokine control group (light blue, p = 0.01). *p < 0.05, **p < 0.01, ***p < 0.001

Fig. 5

Elevated kynurenine (KYN)/tryptophan (TRP) ratio is related to dorsolateral prefrontal cortex (DLPFC) volume and attention in patients with schizophrenia (SCZ) who display elevated peripheral cytokine levels. a Comparison of plasma KYN/TRP ratio in patients with schizophrenia who display high cytokines levels to patients with SCZ who display low cytokine levels and healthy controls with high and low cytokine levels. Patients with SCZ who display elevated proinflammatory cytokines (high) displayed significantly elevated KYN/TRP ratio compared to patients with schizophrenia who displayed low cytokine levels (SCZ low) and healthy controls who displayed low (Con low) and high (Con high) cytokine levels. *p < 0.05, **p < 0.01. b In SCZ patients with high proinflammatory cytokines, a significant negative correlation was detected between KYN/TRP ratio and the attention domain, indicating worse attention performance with elevated KYN/TRP ratio. c In SCZ patients with high proinflammatory cytokines, a significant negative correlation was detected between KYN/TRP ratio and dorsolateral prefrontal cortex (DLPFC) volume