The interaction between autophagy and inflammation in Schizophrenia: insight into mTOR-PI3K/Akt pathways and glial phenotype expression

Abstract

Autophagy can remove endogenous inflammasome and reduce pro-inflammatory cytokine releases. While, over-expression of proinflammatory cytokines may inhibit autophagy. The mTOR is a major regulator of the autophagic process, in which PI3K/Akt pathway underlies the upstream of mTOR and modulates its activity. Both inflammatory response and mTOR-PI3K/Akt expressions were up-regulated in schizophrenia. However, the inter-relationship between chronic inflammation and autophagy, whether inflammation suppresses autophagy via PI3K/Akt/mTOR signaling pathway, and how the imbalance between two immunities causes neuroinflammation and neuropathological changes remain unknown in schizophrenia. Thus, this study determined relationship between inflammation and PI3K/Akt/mTOR pathway in schizophrenia patients (SZ), and between autophagy and glia inflammatory/neuroprotective phenotypes in a mouse model of schizophrenia.66 SZ and 44 healthy controls (CT) were enrolled. Clinical data as well as blood samples were collected. When compared to CT, peripheral autophagy factors MDC stain, and LC3 expression and autophagy activity were decreased, while the concentration of autophagy inhibitor P62, pro-inflammatory factors IL-1β, IL-6 and TNF-α concentrations were increased, and anti-inflammatory factors IL-10 and IL-4 were decreased in SZ. Blood microglia M1 marker IBA1 and astrocyte A1 S100B were up-regulated, while M2 CD206 and A2 P11 were downregulated. A negative correlation between inflammation and autophagy, and synaptic protein Beclin1 and MAP expression were found in SZ lymphocytes. In SZ lymphocytes, the PI3K/Akt/mTOR pathway was activated at both mRNA and protein levels. Then, IL-1 and IL-6 treatment significantly increased, while IL-10 decreased LC3 and Beclin 1 expression in SZ lymphocytes. Furthermore, 3-MA, an autophagy inhibitor, increased NLRP3, ASC, Caspase 1 and pro-inflammatory cytokines IL-1b and IL-6.Mouse model of schizophrenia induced by PolyI:C showed schizophrenia-like behaviors, such as increased spontaneous, impaired cognition and defected sensory-motor gating. In the brain, changes in proinflammatory cytokines, autophagy factors, glial phenotype patterns and synaptic protein were similar to peripheral changes in SZ. More important, clozapine or autophagy agonist RAPA reversed schizophrenia-like behavioral and neuropathological abnormalities, which were aborted by 3-MA.These data for the first time demonstrated imbalance between inflammation and autophagy may contribute to the neuropathology of schizophrenia.