Magnesium/Zinc Protect Against Sepsis By Blocking GSDMD N-Terminal-Induced Pyroptosis

Hypomagnesemia is a significant risk factor for critically ill patients to develop sepsis,a life-threatening disease with a mortality rate over 25%.Our clinic data analysis showed that hypomagnesemia is associated with a decreased monocyte count in septic patients.At the cellular level,we found that Mg2+inhibits pyroptosis.Specifically,Mg2+limits the oligomerization and membrane localization of gasdermin D N-terminal(GSDMD-NT)upon the activation of either the canonical or non-canonical pyroptotic pathway.Mechanistically,we demonstrated that Ca2+influx is a prerequisite for the function of GSDMD-NT.Mg2+blocks Ca2+influx by inhibiting the ATP-gated Ca2+channel P2X7,thereby impeding the function of GSDMD-NT and inhibiting lipopolysaccharide(LPS)-induced non-canonical pyroptosis.Furthermore,Mg2+administration protects mice from LPS-induced lethal septic shock.We also test other divalent ions,zinc can also directly inhibit pyroptosis caused by GSDMD-NT.Prior supplementation of zinc either in bacteria and aseptic infection induced septic mice can improve the survival rate.Together,our data reveal the underlying mechanism of how Mg2+ or Zn2+ inhibits pyroptosis and suggest potential clinic applications of magnesium or zinc supplementation for sepsis prevention and treatment.