Schizophrenia (SZ) is characterized by immune dysregulation and decreased autophagy. However, the mechanistic interplay between these two processes remains unclear. This study aimed to explore the relationship between autophagy and inflammation in SZ patients and a maternal immune activation (MIA)-induced SZ mouse model. Autophagic activity and inflammatory markers were assessed in peripheral blood mononuclear cells (PBMCs) from SZ patients and healthy controls using flowcytometry, Western blotting, and qPCR. Cytokine modulation experiments were conducted in vitro to determine causal relationships. Behavioral, molecular, and neurochemical analyses were performed in MIA-induced SZ-like mice, with or without mTOR inhibitor rapamycin treatment, to assess the role of mTOR-regulated autophagy in vivo. SZ patients exhibited reduced autophagic-lysosome function in PBMCs, evidenced by decreased monodansylcadaverine-positive cells, Beclin-1, LC3B/LC3A, LAMP1, and cathepsin D, alongside increased p62 levels, accompanied by hyperactivation of the PI3K/AKT/mTOR pathway and ULK1 inhibition. These changes were associated with elevated inflammatory markers, including IL-1β, IL-6, IFN-γ, and NLRP3 inflammasome components (NLRP3, ASC, caspase-1). Pharmacological inhibition of autophagy further amplified inflammatory gene expression in vitro, while IL-10 treatment restored LC3B expression, which suppressed by IL-1β/IL-6. MIA mice showed SZ-like behaviors, reduced hippocampal Beclin-1, glial polarization imbalance, cortical neuroinflammation, and monoaminergic disruptions. Rapamycin-induced mTOR inhibition restored autophagy and reversed these abnormalities. Our findings demonstrated that hyperactivation of mTOR suppressed autophagy, leading to sustained elevation of pro-inflammatory cytokines in SZ. Inhibition of mTOR restored autophagic activity, thereby reducing neuroinflammation and glial pro-inflammatory activation, suggesting autophagy as a promising therapeutic target for SZ.
Yan et al. (2026) studied this question.