Liver-derived complement component 3 promotes the susceptibility to stress-induced depression by impairing...

Chronic stress can trigger major depressive disorder through peripheral immune factors. Enhanced circulating levels of complement component 3 (C3), a key innate immunity molecule that is predominantly produced by the liver, have been observed in depressed patients. However, the role of liver-derived C3 in the regulation of behavior under chronic stress remains ambiguous. Here, we found that liver-derived C3 critically contributes to stress susceptibility and blood-brain barrier (BBB) impairment in the nucleus accumbens (NAc) by inhibiting endothelial cell claudin-5, a pivotal tight junction protein for BBB integrity. In three mouse models of depression, hepatic C3 expression was notably increased in mice, with no comparable changes in other peripheral organs. Genetic ablation of C3 ameliorated chronic social defeat stress (CSDS)-induced increases in NAc BBB permeability and depressive-like behavior, and this amelioration was reversed upon re-expression of hepatic C3. Consistently, knockdown of hepatic C3 similarly improved these deleterious effects induced by CSDS. Furthermore, overexpression of hepatic C3 was sufficient to induce depressive-like behavior following subthreshold social stress. Hepatic C3 manipulation bidirectionally regulated expression of claudin-5 in NAc endothelial cells. Mechanistically, the liver-derived C3 suppressed claudin-5 expression in brain endothelial cells and increased stress susceptibility in mice through the C3a receptor-CCAAT/enhancer-binding protein-α signaling pathway in the NAc. Moreover, corticosterone upregulated hepatic C3 release by activation of nuclear factor-κB (NF-κB). Taken together, these results demonstrate that liver-derived C3 promotes susceptibility to depression by increasing BBB permeability under chronic stress, and propose targeting hepatic C3 as a promising therapeutic strategy for depression.