Peripheral toll-like receptor expression indicates distinct innate immune signatures in schizophrenia spectrum and
Julia Karska1, Szymon Kowalski1, Kamila Rudy1
1Department of Psychiatry, Wroclaw Medical University, Pasteura 10 Street, 50-367 Wroclaw, Poland.
Background:
Toll-like receptors (TLRs) are key pattern-recognition receptors initiating inflammatory signaling, and their peripheral mRNA levels may reflect disorder-specific innate immune activation. Dysregulation of innate immunity has been implicated across schizophrenia spectrum disorders (SSD) and mood disorders, yet no quantitative synthesis of TLR expression has been available.
Methods:
The review protocol was registered in PROSPERO (CRD420251146982). MEDLINE, Embase, CINAHL, Cochrane Library, and Web of Science were searched from the inception date to September 2025 for studies quantifying peripheral blood TLR1-TLR10 mRNA in SSD or mood disorders relative to healthy controls. Random-effects meta-analyses were performed using Hedges' g, along with sensitivity analyses and meta-regressions.
Results:
Twenty-six studies met the inclusion criteria, comprising 678 individuals with SSD, 523 with mood disorders, and 1182 healthy controls. In SSD, TLR4, TLR8, and TLR10 showed significantly elevated expression (g = 0.26 - 0.31, pFDR < 0.05). In mood disorders, TLR2, TLR5, and TLR6 were significantly upregulated (g = 0.23 - 0.32, pFDR < 0.05).
Conclusions:
SSD and mood disorders are each associated with distinct patterns of elevated peripheral blood TLR expression relative to healthy controls. These disorder-specific patterns - a broader, multimicrobial profile in SSD versus a more restricted, predominantly antibacterial one in mood disorders - suggest partly distinct innate immunopathological pathways. The findings support the relevance of TLR-based immunophenotyping across diagnostic groups. Longitudinal, experimental, and multi-omics studies are needed to provide further mechanistic insights.
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