The hypersecretion of cytokines triggers life-threatening systemic inflammatory response syndrome(SIRS),leading to multiple organ dysfunction syndrome(MODS)and mortality.Although both coagulopathy and necroptosis have...The hypersecretion of cytokines triggers life-threatening systemic inflammatory response syndrome(SIRS),leading to multiple organ dysfunction syndrome(MODS)and mortality.Although both coagulopathy and necroptosis have been identified as important factors in the pathogenesis of SIRS,the specific cell types that undergo necroptosis and the interrelationships between coagulopathy and necroptosis remain unclear.In this study,we utilized visualization analysis via intravital microscopy to demonstrate that both anticoagulant heparin and nonanticoagulant heparin(NAH)pretreatment protect mice against TNF-α-induced mortality in SIRS.Moreover,the deletion of Mlkl or Ripk3 resulted in decreased coagulation and reduced mortality in TNF-α-induced SIRS.These findings suggest that necroptosis plays a key role upstream of coagulation in SIRS-related mortality.Furthermore,using a genetic lineage tracing mouse model(Tie2-Cre;Rosa26-tdT),we tracked endothelial cells(ECs)and verified that EC necroptosis is responsible for the vascular damage observed in TNF-α-treated mice.Importantly,Mlkl deletion in vascular ECs in mice had a similar protective effect against lethal SIRS by blocking EC necroptosis to protect the integrity of the endothelium.Collectively,our findings demonstrated that RIPK3–MLKL-dependent necroptosis disrupted vascular integrity,resulting in coagulopathy and multiorgan failure,eventually leading to mortality in SIRS patients.These results highlight the importance of targeting vascular EC necroptosis for the development of effective treatments for SIRS patients.展开更多
基金supported by grants from the National Key Research and Development Program of China(2022YFA0807300)the National Natural Science Foundation of China(32270803,32300630,82272181,T2293734)+2 种基金the Shanghai Excellent Academic/Technical Leader Program(22XD1404500)the Shanghai Science and Technology Commission(23141902800)the China Postdoctoral Science Foundation(2020M671261).
文摘The hypersecretion of cytokines triggers life-threatening systemic inflammatory response syndrome(SIRS),leading to multiple organ dysfunction syndrome(MODS)and mortality.Although both coagulopathy and necroptosis have been identified as important factors in the pathogenesis of SIRS,the specific cell types that undergo necroptosis and the interrelationships between coagulopathy and necroptosis remain unclear.In this study,we utilized visualization analysis via intravital microscopy to demonstrate that both anticoagulant heparin and nonanticoagulant heparin(NAH)pretreatment protect mice against TNF-α-induced mortality in SIRS.Moreover,the deletion of Mlkl or Ripk3 resulted in decreased coagulation and reduced mortality in TNF-α-induced SIRS.These findings suggest that necroptosis plays a key role upstream of coagulation in SIRS-related mortality.Furthermore,using a genetic lineage tracing mouse model(Tie2-Cre;Rosa26-tdT),we tracked endothelial cells(ECs)and verified that EC necroptosis is responsible for the vascular damage observed in TNF-α-treated mice.Importantly,Mlkl deletion in vascular ECs in mice had a similar protective effect against lethal SIRS by blocking EC necroptosis to protect the integrity of the endothelium.Collectively,our findings demonstrated that RIPK3–MLKL-dependent necroptosis disrupted vascular integrity,resulting in coagulopathy and multiorgan failure,eventually leading to mortality in SIRS patients.These results highlight the importance of targeting vascular EC necroptosis for the development of effective treatments for SIRS patients.
