Targeting TLR9 reduces chronic stress-associated neuroinflammation and improves social behavior in a mouse model

Chronic stress is a major risk factor for neuropsychiatric disorders and promotes neuroinflammation contributing to network dysfunction and behavior deficits. Emerging work implicates microglia mediated synaptic remodeling in stress-related social deficits, but the upstream innate immune sensors that initiate these responses remain unclear. Toll-like receptor 9 (TLR9) is a key innate immune receptor which initiates proinflammatory response by recognizing exogenous pathogens and cellular DNA released from damaged cells leading to neuroinflammation. However, it’s role in the brain’s response to chronic stress-induced immune and behavioral changes is not known yet. Using a mouse model of chronic restraint stress (RS), we tested whether TLR9 contributes to stress-evoked neuroimmune and behavioral changes. RS increased TLR9 expression in microglia and elevated pro-inflammatory cytokines and chemokines in the prefrontal cortex (PFC). RS also reduced the expression of synaptic trafficking protein Ras-associated binding protein 4 (RAB4), a small GTPase that has been previously implicated in depression pathophysiology and antidepressant response. Treatment with ODN 2088, a TLR9 antagonist significantly attenuated the stress-induced social behavior deficits. Also, the changes in the levels of cytokines, chemokines and RAB4 following RS were attenuated by ODN 2088 treatment. These findings identify TLR9 as a mediator linking chronic stress to microglial activation and social behavior impairment. Targeting TLR9 signaling may offer a therapeutic strategy for mitigating inflammation and behavioral abnormalities associated with chronic stress.