The NLRP3 inflammasome functions as an inflammatory driver,but its relationship with lipid metabolic changes in early sepsis remains unclear.Here,we found that GITR expression in monocytes/macrophages was induced by l...The NLRP3 inflammasome functions as an inflammatory driver,but its relationship with lipid metabolic changes in early sepsis remains unclear.Here,we found that GITR expression in monocytes/macrophages was induced by lysophosphatidylcholine(LPC)and was positively correlated with the severity of sepsis.GITR is a costimulatory molecule that is mainly expressed on T cells,but its function in macrophages is largely unknown.Our in vitro data showed that GITR enhanced LPC uptake by macrophages and specifically enhanced NLRP3 inflammasome-mediated macrophage pyroptosis.Furthermore,in vivo studies using either cecal ligation and puncture(CLP)or LPS-induced sepsis models demonstrated that LPC exacerbated sepsis severity/lethality,while conditional knockout of GITR in myeloid cells or NLRP3/caspase-1/IL-1βdeficiency attenuated sepsis severity/lethality.Mechanistically,GITR specifically enhanced inflammasome activation by regulating the posttranslational modification(PTM)of NLRP3.GITR competes with NLRP3 for binding to the E3 ligase MARCH7 and recruits MARCH7 to induce deacetylase SIRT2 degradation,leading to decreasing ubiquitination but increasing acetylation of NLRP3.Overall,these findings revealed a novel role of macrophage-derived GITR in regulating the PTM of NLRP3 and systemic inflammatory injury,suggesting that GITR may be a potential therapeutic target for sepsis and other inflammatory diseases.展开更多
基金supported by grants from the National Natural Science Foundation of China(31970893,32270976)the Natural Science Foundation of Guangdong Province(2022A1515012541)+4 种基金the Guangdong Natural Science Fund for Distinguished Young Scholars(2016A030306004)the Fundamental Research Funds for the Central Universities(2023kypt18,2023ptpy67,19ykzd39,19ykpy43)the China Postdoctoral Science Foundation(2022M723661)the 111 Project(No.B12003,B13037)the Open Project of the Key Laboratory of Tropical Disease Control(Sun Yat-sen University),Ministry of Education(2020kfkt08).
文摘The NLRP3 inflammasome functions as an inflammatory driver,but its relationship with lipid metabolic changes in early sepsis remains unclear.Here,we found that GITR expression in monocytes/macrophages was induced by lysophosphatidylcholine(LPC)and was positively correlated with the severity of sepsis.GITR is a costimulatory molecule that is mainly expressed on T cells,but its function in macrophages is largely unknown.Our in vitro data showed that GITR enhanced LPC uptake by macrophages and specifically enhanced NLRP3 inflammasome-mediated macrophage pyroptosis.Furthermore,in vivo studies using either cecal ligation and puncture(CLP)or LPS-induced sepsis models demonstrated that LPC exacerbated sepsis severity/lethality,while conditional knockout of GITR in myeloid cells or NLRP3/caspase-1/IL-1βdeficiency attenuated sepsis severity/lethality.Mechanistically,GITR specifically enhanced inflammasome activation by regulating the posttranslational modification(PTM)of NLRP3.GITR competes with NLRP3 for binding to the E3 ligase MARCH7 and recruits MARCH7 to induce deacetylase SIRT2 degradation,leading to decreasing ubiquitination but increasing acetylation of NLRP3.Overall,these findings revealed a novel role of macrophage-derived GITR in regulating the PTM of NLRP3 and systemic inflammatory injury,suggesting that GITR may be a potential therapeutic target for sepsis and other inflammatory diseases.
