IRGM restrains NLRP3 inflammasome activation by mediating its SQSTM1/p62-dependent selective autophagy

Abstract

IRGM is an established genetic risk factor for Crohn disease (CD) and several other inflammatory disorders. However, the mechanisms employed by IRGM to restrain the inflammation are not known. In our recent study, we showed that IRGM negatively regulates NLRP3 inflammasome activation. IRGM employs 2 parallel approaches to constrain inflammasome activation. First, IRGM directly interacts with NLRP3 and PYCARD/ASC, and mediates their SQSTM1/p62-dependent macroautophagic/autophagic degradation. Second, IRGM impedes inflammasome assembly by blocking the polymerization of NLRP3 and PYCARD. We also found that IRGM suppresses NLRP3-mediated exacerbated outcomes of dextran sodium sulfate (DSS)-induced colitis in a mouse model. Taken together, this study presents evidence that IRGM can directly regulate inflammation and protect from inflammatory diseases.

Salvia miltiorrhiza-Derived Sal-miR-58 Induces Autophagy and Attenuates Inflammation in Vascular Smooth Muscle Cells

“…Because it has been demonstrated that autophagy has important effects on the induction of the inflammatory reaction, 6 , 24 we investigated the relationship between Sal-miR-58-induced autophagy and inflammation in Ang II-treated VSMCs. Western blot analysis showed that treating VSMCs with Ang II clearly reduced the expression of Beclin1 and Atg5, which was reversed by Sal-miR-58 transfection, as evidenced by increased expression of Beclin1 and Atg5 as well as by enhanced conversion of LC3BI to LC3BII ( Figure 3 A).…”

From mice to humans: Unravelling the genetic levers of NASH

“…5 Beyond reduction of hepatocyte lipids by lipophagy, and the removal of damaged mitochondria by mitophagy, IRGM has been shown to directly bind to NLRP3 and inhibit activation by disturbing its oligomerization with ASC, and also to increase autophagic degradation of NLRP3 and ASC. 6,7 Further evidence of control of inflammation by IRGM comes from its ability to reduce activation of cGAS-STING and RIG-I-MAVS pathways. 8 Collectively these data suggest that the full impact of differential IRGM expression in NASH may extend beyond increased steatosis to include increased inflammation, and possibly fibrosis.…”

Crosstalks between inflammasome and autophagy in cancer

“…Recent studies have demonstrated that IRGM is a key negative regulator of NLRP3 inflammasome activation by interacting with NLRP3 and ASC and subsequently inhibiting inflammasome assembly [71]. In line with this, IRGM mediates the autophagic degradation of NLRP3 components [72]. However, there is still relatively less known regarding the function of IRGM in cancer.…”