Abstract
NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been implicated in a variety of inflammatory disorders, and its activation should be tightly controlled to avoid detrimental effects. NLRP3 protein expression is considered as the rate-limiting step for NLRP3 inflammasome activation. In this study, we show that galectin-9 (encoded by lgals9) attenuated NLRP3 inflammasome activation by promoting the protein degradation of NLRP3 in primary peritoneal macrophages of C57BL/6J mice. Lgals9 deficiency enhances NLRP3 inflammasome activation and promotes NLRP3-dependent inflammation in C57BL/6J mice in vivo. Mechanistically, galectin-9 interacts with NLRP3, promotes the formation of NLRP3/p62 (an autophagic cargo receptor, also known as SQSTM1) complex, and thus facilitates p62-dependent autophagic degradation of NLRP3 in primary peritoneal macrophages of C57BL/6J mice and HEK293T cells. Therefore, we identify galectin-9 as an "eat-me" signal for selective autophagy of NLRP3 and uncover the potential roles of galectins in controlling host protein degradation. Furthermore, our work suggests galectin-9 as a priming therapeutic target for the diseases caused by improper NLRP3 inflammasome activation.