Type 2 Diabetes Promotes the Microglial Pyroptosis by Activating NLRP3 Inflammasome to Impede Remyelination After Spinal Cord Injury.

Diabetes hinders nerve recovery after spinal cord injury (SCI). The complex pathological factors of diabetes increase the difficulty of treating diabetes combined with SCI. Maintaining normal microglial function is essential for SCI recovery. However, it is unclear whether diabetes hinders nerve recovery after SCI by influencing normal microglial function. This study explored the role and regulatory mechanism of diabetes in microglial function during SCI recovery. We constructed a type 2 diabetes (T2D) combined with SCI mouse model and confirmed that T2D hinders nerve repair after SCI. T2D blocked phagocytizing function of microglia in SCI mice, which results in increased myelin debris accumulation and poor remyelination. A mechanistic study demonstrated that T2D triggers activation of NLRP3 inflammasome by activating the RAGE-ROS-TXNIP axis and then induces excessive microglial pyroptosis, which consequently leads to considerable loss of microglia after SCI. Verapamil (VRP; a TXNIP inhibitor) treatment confirmed that TXNIP is necessary for NLRP3 inflammasome activation. Conditional microglial Caspase-1 gene knockout (KO) mice also confirmed that excessive microglial pyroptosis is an important inducing event for more severe nerve damage in T2D combined with SCI mice. Moreover, this T2D effect on increased microglial pyroptosis was also effectively reversed by N-acetyl-l-cysteine (NAC; an antioxidant) and N-benzyl-4-chloro-N-cyclohexylbenzamide (FPS-ZM1; a RAGE inhibitor). In conclusion, this study revealed that T2D induces increased microglial pyroptosis by activating the RAGE-ROS-NLRP3 axis, and then blocks remyelination after SCI, which strongly suggests that microglial pyroptosis may be the key target for treating T2D combined with SCI.