S100A8 dysregulation as a neuroimmune nexus: Bridging childhood inflammatory infections to adult schizophrenia-like behaviors via the ELNI model.

Abstract

OBJECTIVE: Emerging evidence suggests that dysregulated neuroimmune pathways are implicated in schizophrenia (SCZ); however, the mechanisms connecting early-life inflammation to adult psychiatric outcomes remain inadequately understood. This study examines the role of the pro-inflammatory alarmin S100A8, a calcium- and zinc-binding protein that significantly influences the regulation of inflammatory processes and immune responses, as a potential convergent hub in pediatric infections and SCZ. Furthermore, the study characterizes the behavioral effects of S100A8 using a novel ELNI model. METHODS: We analyzed gene expression datasets from blood and brain of SCZ patients and pediatric infections (GEO accessions: GSE53987, GSE73464, GSE38484) using limma. Genetic regulation of S100A8 was examined by integrating GWAS (PGC-SCZ3) and TWAS (PsychENCODE) data. An ELNI mouse model was established via LPS injections on postnatal days 24-30. Behavioral tests, qRT-PCR, and immunofluorescence were used to assess neuroinflammation and behavioral phenotypes. RESULTS: S100A8 was upregulated in the blood and postmortem brain tissues of SCZ patients, as well as in the blood of children with bacterial infections. The rs10908557 risk allele was associated with increased S100A8 expression. LPS-induced early-life inflammation in mice led to transient growth impairment, prepulse inhibition deficits, and depressive-like behaviors. S100A8 overexpression in the hippocampus correlated with microglial activation and impaired sensorimotor gating. CONCLUSION: S100A8 serves as a shared genetic and transcriptional biomarker between pediatric infections and SCZ. Early-life inflammation induces persistent SCZ-relevant behaviors through S100A8-mediated neuroinflammation. The ELNI model offers a translational platform for studying neurodevelopmental origins of psychiatric disorders, highlighting S100A8 as a potential biomarker and therapeutic target.