Rapamycin regulates macrophage activation by inhibiting NLRP3 inflammasome-p38 MAPK-NFκB pathways in autophagy- and p62-dependent manners

Abstract

Excessive and prolonged activation of macrophages underlies many inflammatory and autoimmune diseases. To regulate activation and maintain homeostasis, macrophages have multiple intrinsic mechanisms, one of which is modulation through autophagy. Here we demonstrate that autophagy induction by rapamycin suppressed the production of IL-1β and IL-18 in lipopolysaccharide- and adenosine triphosphate-activated macrophages at the post-transcriptional level by eliminating mitochondrial ROS (mtROS) and pro-IL1β in a p62/SQSTM1-dependent manner. In addition, rapamycin activated Nrf2 through up-regulation of p62/SQSTM1, which further contributed to the reduction of mtROS. Reduced IL-1β subsequently diminished the activation of p38 MAPK-NFκB pathways, leading to transcriptional down-regulation of IL-6, IL-8, MCP-1, and IκBα in rapamycin-treated macrophages. Therefore, our results suggest that rapamycin negatively regulates macrophage activation by restricting a feedback loop of NLRP3 inflammasome-p38 MAPK-NFκB pathways in autophagy- and p62/SQSTM1-dependent manners.