SR-A1 Mediates Chronic Stress-induced Depression

Objectives:Depression is a debilitating condition with a profound impact on quality of life for millions of people worldwide. Proinflammatory processes and their effects on microglia function are important promoting factors in the pathogenesis of stress-induced depressive disorders. Class A1 scavenger receptor(SR-A1) is up-regulated in mice brains with permanent occlusion of middle cerebral artery(MCAO), and SR-A1 promotes cerebral ischemic injury by pivoting microglia/macrophage polarization. We hypothesized that SR-A1 might play a role in stress-induced depression by regulating neuroinflammation.Methods:(1)Mice were subjected to chronic unpredictable mild stress to induce depression. Mice were divided into four groups, â‘  WT; â‘¡ WT+CMS; â‘¢ Sr-a1-/-; â‘£Sr-a1-/-+CMS. Depressive-like behaviors were evaluated by behavioral experiments.(2)Brain tissues were collected from depressive mice and the damage of cortical neurons was measured by Nissen staining.(3)The total RNA was extracted from mice brain tissues and reversed qPCR was performed, subsequently. The m RNA levels of SR-A1, inflammatory factors, proteins mediating synaptic plasticity, neurotrophic factors and kynurenine metabolic enzymes were assayed.(4)Cytoplasmic proteins were extracted from the brain tissue. Then the expression levels of SR-A1 and the activation of P65 pathway were detected by Western blot.(5)Mice were received bone marrow transplantation and recovered for 4 weeks, then underwent chronic unpredictable mild stress to induce depression model. Depressive-like behaviors were evaluated by behavioral experiments.Results:WT mice subjected to chronic unpredictable mild stress for 4 weeks up-regulated the expression of SR-A1 and displayed significant depression-like behavioral changes, including decreased sucrose preference, significantly prolonged immobility times of forced swim and tail suspension test compared with Sr-a1-/- CMS modeling group. We found the ablation of SR-A1 showed ameliorated CNS inflammation, less pro-inflammatory cytokines and inhibited kynurenine metabolic pathway, but improved synaptic plasticity, brain derived neurotrophic factor after CMS. Furthermore, Sr-a1-/- mice inhibited the activation of p65. The results of bone marrow transplantation indicated that Sr-a1-/- mice were resistant to depression-like phenotypes were mediated on microglia rather than periphery infiltrating macrophages.Conclusions:Sr-a1-/- mice were resistant to depression-like symptoms induced by chronic unpredictable mild stress, which indicated that SR-A1 might be involved in mediating the process by pivoting microglia polarization toward M1 phenotype, and increasing neuroinflammation and the imbalance of kynurenine metabolic pathway. SR-A1 could be a novel potential therapeutic target for the depression.