Chronic Stress Promotes Depression-Like Behavior through Hepatocyte-Derived C3-Mediated Blood-Brain Barrier Disruption

摘要

Objective: Hepatic dysfunction is closely related to psychiatric disorders. Chronic stress can trigger liver inflammation. As the primary source of circulating complement component 3(C3), the liver's inflammatory state may drive alterations in peripheral immune signaling. This study investigates the mechanism by which liver-derived C3 under stress transmits to the central nervous system to regulate behavior. Methods: A chronic social defeat stress(CSDS) mouse model of depression was used. Behaviors were assessed using social interaction, sucrose preference, forced swimming, and tail suspension tests. The changes in complement protein levels were analyzed by western blotting and enzyme-linked immunosorbent assay. Viral vectors were used to manipulate C3 expression. Co-culture systems examined the effect of stressed hepatocytes on claudin-5(Cldn5) in brain endothelial cells. The blood-brain barrier(BBB) permeability, microglial synaptic phagocytosis, and synaptic structures were observed by confocal/electron microscopy. Dendritic spine dynamics were monitored by two-photon microscopy. Results:(1) CSDS induced depressive-like behaviors such as social avoidance and anhedonia in mice.(2) In the animal model of CSDS, circulating C3 was upregulated and associated with an increase in hepatic C3, which was induced by stress hormones through the NF-κB activation.(3) The up-regulated hepatic C3 was sufficient to induce depressive-like behaviors following subthreshold social stress.(4) The liver-derived C3 inhibited Cldn5 expression in brain endothelial cells through the C3a receptor(C3aR)-CCAAT/enhancerbinding protein-α(C/EBP-α) signaling pathway, elevating BBB permeability. Knockdown of hepatocyte C3 largely improved CSDS-induced BBB breakdown and behavioral abnormalities.(5) CSDS increases microglial numbers in the mPFC and specifically enhances their phagocytic activity toward excitatory synapses.(6) CSDS induces synapse loss in the mPFC of mice and impairs synaptic remodeling and transmission.(7) Complement C3 drives microglial-mediated synaptic elimination during CSDS. Knockout of C3 protects against CSDS-induced impairment of synaptic transmission, cortical underconnectivity and behavioral consequences in mice. Conclusion: This study uncovers a liver-brain axis where hepatic C3 mediates CSDS-induced depression. Stress elevates liver-derived C3, which disrupts BBB integrity via endothelial C3aR/C/EBP-α signaling, leading to microgliadependent synaptic loss in the mPFC and depressive behaviors.

关键词

depression / liver / complement system / microglia / synaptic prunning