In the current study, caspase-1–dependent, but not caspase-11–mediated, endothelial pyroptosis was found both in LPS-primed endothelial cells stimulated by HNP-1 and in the DEFA1/DEFA3 risk-variant transgenic mice after sepsis progression, where HNP-1–dependent damage was triggered through signaling by P2X7 receptor. Here, CASP1 is linked to Sepsis.