Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome

TLDR

Dying cells can activate innate immunity, triggering sterile inflammation. The study demonstrates that necrotic cells activate the Nlrp3 inflammasome, leading to IL‑1β release. Necrotic cells from pressure, hypoxia, or complement damage activate Nlrp3 via mitochondrial ATP, inducing IL‑1β release and neutrophil influx; Nlrp3 deficiency reduces neutrophil recruitment, renal dysfunction, and mortality in ischemic tubular necrosis, showing that Nlrp3 inhibition can lessen acute inflammation and tissue damage.

Abstract

Dying cells are capable of activating the innate immune system and inducing a sterile inflammatory response. Here, we show that necrotic cells are sensed by the Nlrp3 inflammasome resulting in the subsequent release of the proinflammatory cytokine IL-1β. Necrotic cells produced by pressure disruption, hypoxic injury, or complement-mediated damage were capable of activating the Nlrp3 inflammasome. Nlrp3 inflammasome activation was triggered in part through ATP produced by mitochondria released from damaged cells. Neutrophilic influx into the peritoneum in response to necrotic cells in vivo was also markedly diminished in the absence of Nlrp3. Nlrp3-deficiency moreover protected animals against mortality, renal dysfunction, and neutrophil influx in an in vivo renal ischemic acute tubular necrosis model. These findings suggest that the inhibition of Nlrp3 inflammasome activity can diminish the acute inflammation and damage associated with tissue injury.