To explore how macrophages perceive intracellular LPS and function in the host at the whole body level, Kumari et al. (98) constructed a conditional knockout of caspase-11 from monocytes/macrophages, neutrophils, and dendritic cells in mice, and found that macrophage/monocyte-specific caspase-11 plays a leading role in mediating the pathological manifestations of endotoxemia, including the activation of GSDMD, IL-1β and IL-18, the release of DAMPs and tissue damage, proving that caspase-11 dependent macrophage pyroptosis is pivotal in the development of sepsis. The gene discussed is GSDMD; the disease is Sepsis.