Deciphering the interplay between peripheral and central cytokine- and kynurenine pathways : importance for the pathophysiology of schizophrenia

Growing evidence suggests a role of low-grade inflammation in the pathophysiology of schizophrenia, giving rise to a dysregulation in neurons containing dopamine and glutamate as well as γ-aminobutyric acid (GABA). In this thesis, a role of peripheral and brain-immune signaling molecules, as well as brain neurotransmitters, was investigated in a wellcharacterized cohort of first-episode psychosis (FEP) patients. Using human monocyte cultures, toll-like receptor (TLR) activation was analyzed to study the production of metabolites along the kynurenine pathway. We found that stimulation of TLR-2, TLR-3, TLR-4, TLR-7/8, and TLR-9 induced the pathway, whereas activation of TLR-1/2, TLR-5, and TLR-2/6 did not. Interestingly, only activation of TLR-3 induced the production kynurenic acid (KYNA), a neuroactive metabolite implicated in psychotic disorders. In FEP patients, the number of blood monocytes, as well as plasma concentrations of the chemokines chitinase-3-like protein 1 (YKL-40) and monocyte chemoattractant protein-1 (MCP-1/CCL2), was elevated compared to healthy controls. In addition, FEP patients displayed elevated plasma levels of interleukin (IL)-18 and the levels associated with the cognitive impairments observed in FEP patients, i.e., reduced speed of processing. Moreover, FEP patients displayed lower GABA levels in the cerebrospinal fluid (CSF) compared to healthy controls. CSF GABA concentrations were negatively correlated with scores of cognitive performance and severity of symptoms. Preliminary data also showed higher CSF dopamine concentrations in FEP patients compared to healthy controls. The results of this thesis strengthen the idea that immune dysfunctions affect tryptophan metabolism as well as GABAergic and dopaminergic neurotransmission in early schizophrenia. Also, the data may provide new opportunities to identify biological markers, urgently needed for the diagnosis of the disorder. LIST OF SCIENTIFIC PAPERS I. Orhan F, Bhat M, Sandberg K, Ståhl S, Piehl F, Karolinska Schizophrenia Project (KaSP) consortium, Svenssson C, Erhardt S, Schwieler L. Tryptophan metabolism along the kynurenine pathway. Downstream of toll-like receptor stimulation in peripheral monocytes. Scandinavian Journal of Immunology, 2016. II. Funda Orhan, Lilly Schwieler, Helena Fatouros-Bergman, Anna Malmqvist, Simon Cervenka, Karin Collste, Lena Flyckt, Lars Farde, Carl M Sellgren, Karolinska Schizophrenia Project (KaSP) consortium, Fredrik Piehl, Göran Engberg, Sophie Erhardt. Increased number of monocytes and plasma levels of MCP-1 and YKL-40 in first-episode psychosis. [Manuscript] III. Orhan F, Fatouros-Bergman H, Schwieler L, Cervenka S, Sellgren CM, Karolinska Schizophrenia Project (KaSP), G Engberg, S Erhardt. Firstepisode psychosis patients display increased plasma IL-18 that correlates with cognitive dysfunction. Schizophrenia Research, 2017. IV. Orhan F, Fatouros-Bergman H, Goiny M, Malmqvist A, Piehl F, Karolinska Schizophrenia Project (KaSP) Consortium, Cervenka S, Collste K, Victorsson P, Sellgren CM, L Flyckt, S Erhardt, G Engberg. CSF GABA is reduced in first episode psychosis and associates to symptoms severity. Molecular Psychiatry, 2017.