Conditional knockout of SIRT1, an NAD+‐dependent deacetylase, in macrophages or endothelial cells counteracts the inhibition of inflammatory cytokine secretion and prevention of endothelial cell permeability by 3,4‐cPP in CLP‐induced septic mice, indicating that the S1P1/SIRT1 axis in both the endothelium and macrophages is essential for survival in sepsis. This evidence concerns the gene S1PR1 and Sepsis.