Meta-analysis of brain and blood transcriptional signatures of neuroimmune dysregulation in Schizophrenia: convergent evidence for excessive complement system activity and CX3CL1-CX3CR1 axis disruption

BACKGROUND: Schizophrenia pathogenesis may involve aberrant synaptic pruning mediated by excessive complement system activity (CSA) and altered microglial function. Microglia and CSA are tightly regulated by neuro-immune regulators (NIREGs) which regulate adverse innate response and play a critical role in the regulation of the synaptic pruning process. This study investigated transcriptional alterations of NIREGs in the brain and blood tissues of individuals living with schizophrenia (SZ individuals) vs. healthy controls (HC). METHODS: Meta-analyses were performed on gene expression data from 532 SZ individuals and 623 HC in postmortem brain tissue, and 197 SZ individuals and 164 HC in peripheral blood. In addition to C4 gene, 9 NIREGs coding genes were analyzed: 3 genes encoding complement regulators (CD46, CD55, CD59), 3 genes encoding "don't eat me signals" (CX3CL1, CD200, CD47) and a further 3 genes encoding their microglial counter-receptors (CX3CR1, CD200R, SIRPα). Exploratory network analysis was performed in brain datasets. RESULTS: In brain tissue, SZ was associated with C4 overexpression and underexpression of CD46 and CX3CL1. Sex-specific transcriptional differences emerged for CD200 (female-specific) and CD59, CX3CR1 (male-specific). In the peripheral blood, CD46, CD55 and CD59 were overexpressed, while CX3CR1 was underexpressed. Brain and blood showed distinct altered expression patterns. However, disruption of the CX3CL1-CX3CR1 axis was observed in both tissues. Network analyses suggested altered co-regulations between astrocytes and microglia or neurons in SZ individuals. CONCLUSIONS: Transcription of NIREGs encoding genes is altered in the brain and blood of SZ individuals, suggesting that immune dysregulation in schizophrenia arises from a combination of C4 overexpression and an altered expression of NIREGS. In SZ individuals, blood CX3CR1 underexpression in the peripheral blood may serve as a peripheral biomarker of the brain CX3CR1-CX3CL1 axis disruption.