The molecular trigger that transduces psychosocial stress into the release of the key pro-inflammatory cytokine interleukin-1β (IL-1β) has been a missing link in stress-related neuropathology. We identify the E3 ubiquitin ligase tripartite motif-containing protein 21 (TRIM21) as this critical upstream regulator. In a rat model of repeated social defeat stress, TRIM21 was upregulated in the hippocampus, brain microvasculature, and peripheral blood mononuclear cells (PBMCs). This upregulation correlated with anxiety-like behavior and cognitive deficits and was more pronounced in females. Mechanistically, TRIM21 directly interacts with and promotes the cleavage of gasdermin D (GSDMD), enabling the formation of membrane pores for the export of mature IL-1β. This TRIM21-GSDMD-IL-1β axis was functional in PBMCs, linking peripheral immune activation to behavioral pathology. In vivo knockdown of TRIM21 systemically attenuated this pathway, reducing IL-1β release and downstream NF-κB activation. This intervention rescued blood-brain barrier integrity, restored hippocampal synaptic density, and attenuated behavioral deficits. Pharmacological inhibition of GSDMD with disulfiram recapitulated the neuroprotective effects of TRIM21 knockdown, validating this axis as a druggable pathway for stress-induced pathology. Using an in vitro neurovascular model, we defined endothelial TRIM21 as a central mediator of this stress-induced inflammatory cascade. These findings establish TRIM21 as a pivotal stress-responsive node, bridging peripheral immune signaling to GSDMD-dependent neuroinflammation and blood-brain barrier disruption, thereby revealing a new mechanistic framework and potential therapeutic target for neuropsychiatric disorders.
Tiwari et al. (Mon,) studied this question.