Macrophage polarization to proinflammatory M1-like or anti-inflammatory M2-like cells is critical to mount a host defense or repair tissue.The exact molecular mechanisms controlling this process are still elusive.Here...Macrophage polarization to proinflammatory M1-like or anti-inflammatory M2-like cells is critical to mount a host defense or repair tissue.The exact molecular mechanisms controlling this process are still elusive.Here,we report that ubiquitin-specific protease 19(USP19)acts as an anti-inflammatory switch that inhibits inflammatory responses and promotes M2-like macrophage polarization.USP19 inhibited NLRP3 inflammasome activation by increasing autophagy flux and decreasing the generation of mitochondrial reactive oxygen species.In addition,USP19 inhibited the proteasomal degradation of inflammasome-independent NLRP3 by cleaving its polyubiquitin chains.USP19-stabilized NLRP3 promoted M2-like macrophage polarization by direct association with interferon regulatory factor 4,thereby preventing its p62-mediated selective autophagic degradation.Consistent with these observations,compared to wild-type mice,Usp19−/−mice had decreased M2-like macrophage polarization and increased interleukin-1βsecretion,in response to alum and chitin injections.Thus,we have uncovered an unexpected mechanism by which USP19 switches the proinflammatory function of NLRP3 into an anti-inflammatory function,and suggest that USP19 is a potential therapeutic target for inflammatory interventions.展开更多
基金This work was supported by the National Key Research and Development Project(2020YFA0908700)the National Natural Science Foundation of China(31870862 and 31700760).
文摘Macrophage polarization to proinflammatory M1-like or anti-inflammatory M2-like cells is critical to mount a host defense or repair tissue.The exact molecular mechanisms controlling this process are still elusive.Here,we report that ubiquitin-specific protease 19(USP19)acts as an anti-inflammatory switch that inhibits inflammatory responses and promotes M2-like macrophage polarization.USP19 inhibited NLRP3 inflammasome activation by increasing autophagy flux and decreasing the generation of mitochondrial reactive oxygen species.In addition,USP19 inhibited the proteasomal degradation of inflammasome-independent NLRP3 by cleaving its polyubiquitin chains.USP19-stabilized NLRP3 promoted M2-like macrophage polarization by direct association with interferon regulatory factor 4,thereby preventing its p62-mediated selective autophagic degradation.Consistent with these observations,compared to wild-type mice,Usp19−/−mice had decreased M2-like macrophage polarization and increased interleukin-1βsecretion,in response to alum and chitin injections.Thus,we have uncovered an unexpected mechanism by which USP19 switches the proinflammatory function of NLRP3 into an anti-inflammatory function,and suggest that USP19 is a potential therapeutic target for inflammatory interventions.
