TRIM21 drives stress-induced neuroinflammation and behavioral deficits via gasdermin D- dependent IL-1β release in a rat model of repeated social defeat

The upstream mechanism that transduces psychosocial stress into the release of the pivotal pro-inflammatory cytokine IL-1β has remained a fundamental gap in understanding neuropsychiatric disorders. Here, we identify tripartite motif-containing protein 21 (TRIM21) as the critical trigger. In a rat model of repeated social defeat, TRIM21 was upregulated in the hippocampus, brain microvessels, and peripheral blood mononuclear cells (PBMCs), correlating with anxiety-like behavior and memory deficits, with females exhibiting a more pronounced pathophysiology. Mechanistically, TRIM21 directly binds to and promotes the cleavage of gasdermin D, facilitating the formation of membrane pores for IL-1β release. This pathway was active in PBMCs, where TRIM21 drove sub-lytic pore formation and IL-1β release, linking peripheral inflammation to behavioral deficits. Critically, in vivo TRIM21 knockdown abrogated this pathway systemically, reducing IL-1β release and NF-κB signaling, which in turn rescued blood-brain barrier integrity, restored synaptic density, and normalized behavior. Using an in vitro blood-brain barrier model, we pinpointed this effect to a TRIM21-IL-1β-p65 axis. We therefore define TRIM21 as the critical node in a stress-responsive circuit, bridging peripheral immune activation to GSDMD-dependent neuroinflammation and blood-brain barrier disruption, thereby providing a mechanistic framework that redefines the pathophysiology of stress-related neuropsychiatric disorders and reveals new avenues for their treatment.