Microglial TIA1 in Lateral Septum Facilitates Chronic Inflammatory Pain via Regulating NF-κB Signaling Pathway

Here, we identified microglial T-Cell Intracellular Antigen 1 (TIA1) in the lateral septum (LS) as a critical driver of chronic inflammatory pain via modulation of the NF-κB signaling pathway. Using a Complete Freund’s Adjuvant (CFA)-induced pain mouse model, we found that microglia exhibited most heightened activation in LS compared to other brain regions, and RNA sequencing further found that dysregulation of NF-κB-related genes and RNA metabolic process in the LS in CFA-induced mice.

Mechanistical studies showed that TIA1 (an RNA-binding protein) facilitated pain by binding to IκBα mRNA to suppress its translation, subsequently enabled NF-κB activation. Conditional knockout (CKO) of microglial TIA1 (TIA1CX3CR1-CKO) in mice significantly elevated pain threshold, pain thresholds was normalized while restoring IκBα expression in LS microglia of TIA1CX3CR1-CKO mice. Pharmacological inhibition of NF-κB phenocopies the analgesic effects of TIA1CX3CR1-CKO, while IκBα is forcibly degraded degradation in CKO mice restores pain sensitivity and NF-κB activity.