Non-redundant roles of caspase-4 and caspase-5 in heme driven- IL-1β release and cell death

Excessive release of heme from red blood cells is a key pathophysiological feature of several disease states including bacterial sepsis, malaria, and sickle cell disease. This hemolysis results in an increased level of free heme that has been implicated in the inflammatory activation of monocytes, macrophages, and endothelium. Here we show that extracellular heme engages human inflammatory caspases, caspase-1, caspase-4, and caspase-5, resulting in the release of IL-1β. Heme-induced IL-1β release was further increased in macrophages from patients with sickle cell disease. Heme activates caspase-1 in an inflammasome-dependent manner, but heme-induced activation of caspase-4 and caspase-5 is inflammasome-independent. Furthermore, we show that caspase-5, but not caspase-4, is essential for heme-induced IL-1β release, while caspase-4 contributes to heme-induced cell death. Together, we have identified that extracellular heme acts as a DAMP that can engage canonical and non-canonical inflammasome activation as a key mediator of inflammation in macrophages.