Immune Alterations in Psychosis: Focus on the JAK-STAT1 Pathway

Changes in immune activity are widely reported in individuals with psychotic disorders. These findings, in conjunction with epidemiological data and recent research demonstrating the influence of the immune system in modulating brain activity and behavior, suggest that these alterations may be related to symptom development and exacerbation. Peripheral immune cells, particularly monocytes and macrophages, are proposed to contribute to increased levels of inflammation in psychosis. While activation of the JAK-STAT1 pathway by IFN-γ is understood to induce the myeloid cell proinflammatory phenotype, there a scarcity of data on this pathway and its relation to clinical measures in the psychosis literature. Measurement of a JAK-STAT1 transcriptional signature (IFNG, CXCL10, IRF1, STAT1 and TLR4) in peripheral blood mononuclear cells from participants with psychosis (n=89) and non-psychiatric controls (n=44) revealed suppressed JAK-STAT1 activity earlier in illness and with increased illness acuity. This decrease did not appear to be related to antipsychotic treatment, and further analyses in participants treated with risperidone monotherapy as well as monocyte and macrophage cell culture experiments indicated a potentiating effect of risperidone on the JAK-STAT1 transcriptional signature, potentially contributing to the increase, or normalization, of the signature in participants with a longer illness duration. To further characterize the monocyte phenotype in relation to illness duration, monocytes were isolated from an independent sample of participants with psychosis (n=14) and controls (n=14) followed by RNA sequencing and gene set enrichment analysis. Participants with a shorter illness duration once again had decreased enrichment of the IFN-γ mediated JAK-STAT1 signature (IFN-γ signature). Interestingly, there was a corresponding increased enrichment of transcriptional signatures related to anti-inflammatory and tissue remodeling phenotypes (including the IL-4 signature), but also of another canonical proinflammatory signature (LPS acute signature). Conversely, in participants with a longer illness duration the was enrichment exclusively of interferon response genes (both IFN-γ and IFN-α signatures). These findings highlight the complexity of immune alterations in psychosis across the course of the illness, demonstrating the need to isolate specific cell types and consider illness context as research continues to uncover the role of circulating immune cells in mediating central nervous system function in health and disease.