Hemolysis-induced lethality involves inflammasome activation by heme

Heme causes inflammation in sterile and infectious conditions, contributing to the pathogenesis of sickle cell disease, malaria, and sepsis, but the mechanisms by which heme operates are not completely understood. Here we show that heme induces IL-1β processing through the activation of the nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome in macrophages. Our results suggest that among NLRP3 activators, heme has common as well as unique requirements to trigger inflammasome activation. In vivo, hemolysis and heme cause inflammasome activation. Importantly, macrophages, inflammasome components, and IL-1R contribute to hemolysis-induced lethality. These results highlight the potential of understanding the molecular mechanisms by which heme is sensed by innate immune receptors as a way to identify new therapeutic strategies to treat the pathological consequences of hemolytic diseases.