Brain Behav Immun. 2026 Apr 22. pii: S0889-1591(26)00516-7. [Epub ahead of print]
106768
Chronic pain is a widespread and debilitating condition, presenting significant clinical, socio-economic, and public health challenges. Microglia, the resident immune cells of the central nervous system, are implicated in the regulation of chronic pain, but the precise mechanisms, particularly brain region-specific contributions, remain poorly understood. In this study, we used a mouse model of complete Freund's adjuvant (CFA)-induced inflammatory pain to explore the role of T-cell intracellular antigen 1 (TIA1), an RNA-binding protein, in microglia. We found that conditional knockout of Tia1 in microglia (Tia1CX3CR1-CKO mice) resulted in a significant reduction in pain sensitivity. Notably, the lateral septum (LS) emerged as a key brain region, where microglial activation was most significantly elevated in response to CFA-induced inflammation. Mechanistically, we discovered that TIA1 binds to and suppresses the translation of IκBα mRNA, triggering NF-κB signaling that contributes to neuroinflammation and neuronal hyperexcitability in the LS. In Tia1CX3CR1-CKO mice, chronic pain was alleviated, accompanied by restored IκBα expression and reduced NF-κB activation in the LS. In contrast, forced degradation of IκBα in the LS of these pain-resistant mice reinstated NF-κB activity and reversed the analgesic effects. These findings uncover a previously unknown post-transcriptional mechanism in microglia, where TIA1 links RNA-binding protein activity to NF-κB-driven neuroinflammation. Our results underscore the lateral septum as a critical region in chronic pain persistence and highlight TIA1 as a promising therapeutic target for intervention.
Keywords: IκBα; LateralSeptum; Microglia; NF-κB; TIA1