TIM3 alleviates microglia-mediated neuroinflammation in neuropathic pain by negatively regulating glycolysis-driven NLRP3 inflammasome activation.

Abstract

Microglia-mediated neuroinflammation has emerged as a potential therapeutic target for neuropathic pain. T-cell immunoglobulin domain and mucin domain-3 (TIM3), which is expressed on various immune cells, has been implicated in inflammation-related diseases. However, its role in neuropathic pain remains unclear. Here, we show that following chronic constriction injury, TIM3 expression is significantly upregulated and plays a protective role by limiting the development and progression of neuropathic pain. Specifically, TIM3 upregulation attenuates neuropathic pain progression and microglia-mediated neuroinflammation, whereas pharmacological inhibition of TIM3 exacerbates pain hypersensitivity. Mechanistically, TIM3 negatively regulates glycolysis, thereby suppressing NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation and preventing further microglia-driven inflammatory responses in vivo and in vitro. Furthermore, both glycolysis and the glycolysis-associated NLRP3 inflammasome are essential for TIM3-mediated neuropathic pain development. Additionally, TIM3 inhibits nuclear factor-kappa B (NF-κB) activation by downregulating glycolysis in vivo and in vitro. Our findings identify TIM3 as a negative regulator of the glycolysis/NLRP3 inflammasome pathway in inflammatory microglia, highlighting its protective role against neuropathic pain. These results suggest that TIM3 is a promising therapeutic target for preventing neuropathic pain.