The caspase 11/gasdermin D pathway is a key driver of stress-induced neuroinflammation and behavioral dysfunction in...

Chronic low-grade inflammation is an established hallmark of stress-related psychiatric disorders. While the canonical NLRP3 inflammasome, which activates caspase 1 and IL1β, has been implicated in stress, the contribution of the non-canonical inflammasome pathway remains unknown. Using a rat model of repeated social defeat, we report the first evidence that psychosocial stress triggers a sex-specific activation of the non-canonical inflammasome pathway in the brain and peripheral immune cells, as evidenced by the cleavage of caspase 11 and its downstream effector, gasdermin D. To establish a causal role, we demonstrated that both genetic knockdown of caspase 11 and pharmacological inhibition of either caspase 11 or gasdermin D significantly reduced stress-induced IL1β release. This reduction in inflammation was accompanied by a broad amelioration of behavioral deficits, including attenuated anxiety and fear acquisition, enhanced fear extinction, reduced synaptic loss, and improved working memory. Crucially, when compared to single-pathway inhibition, the combined targeting of both canonical and non-canonical pathways demonstrated significantly higher efficacy in mitigating neuroinflammation, preventing hippocampal dendritic spine loss, and mitigating behavior deficits. Additionally, this combination therapy also reduced peripheral inflammation. Corroborating these in vivo findings, ex vivo studies using peripheral blood mononuclear cells isolated from stressed rats confirmed that the non-canonical caspase 11/gasdermin D pathway works in concert with the NLRP3 canonical pathway to drive IL1β induction. Our findings reveal a novel dual-inflammasome mechanism underlying psychosocial stress-induced pathophysiology and establish a foundational rationale for co-targeting the NLRP3 and caspase 11/gasdermin D pathways as a promising transdiagnostic therapeutic strategy.