Cutting Edge: Necrosis Activates the NLRP3 Inflammasome

Abstract

Cells undergoing necrosis release endogenous danger signals that possess proinflammatory potential. In this study we show that mature IL-1β and IL-18 are released by necrotic cells but not by apoptotic cells. We identify 7-bromoindirubin-3′-oxime, an indirubin oxime derivative that induces necrosis, as a potent inducer of caspase-1 activation and release of mature IL-1β and IL-18. Inflammasome activation was triggered by other necrosis-inducing treatments but was not observed in response to apoptosis-inducing stimuli. Necrosis-induced inflammasome activation was mediated by the NLRP3 and ASC molecules. Release of IL-18 and IL-1β in response to necrosis-inducing stimuli was observed in THP-1 macrophages and the MSTO-211H human mesothelioma cell line independently of LPS priming. Using the in vivo model of naphthalene-induced airway epithelial cell injury, we showed that necrosis activates the ASC inflammasome in vivo. Our study identifies a new mechanism through which necrosis generates proinflammatory molecules that contributes to the sterile inflammatory response.

The Inflammasomes in Kidney Disease

“…77 ATP in the mitochondrial fraction of necrotic cells activates the NLRP3 inflammasome through P2X 7 receptors. 25,63,74 Consistent with these data, P2X 7 Ϫ/Ϫ mice exhibit less tubular injury and reduced inflammation and fibrosis after UUO compared with wild-type mice. 78 In addition to ATP, other cellular factors also activate the NLRP3 inflammasome and play a role in chronic kidney disease, including the extracellular matrix components biglycan, hyaluronan.…”

“…For example, cellular necrosis triggers NLRP3 activation in macrophages by release of ATP or uric acid. 25 The multitude of NLRP3 triggers underscores the likely function of this inflammasome as a sensor of cellular stress or injury operating through a single common pathway. 26 -28 For example, the activation of NLRP3 occurs after endolysosomal stress and the activation of lysosomal proteases such as cathepsin B.…”

The NLRP3 Inflammasome Promotes Renal Inflammation and Contributes to CKD

“…16 For example, ATP in the mitochondrial fraction of necrotic cells activates the Nlrp3 inflammasome via P2X 7 receptors. 15,22,35,39 Consistent with these data, P2X 7 Ϫ/Ϫ mice exhibit less tubular injury as well as reduced inflammation and fibrosis after UUO compared with their wild-type counterparts. 40 In addition to ATP, other cellular factors have also been shown to activate the NLRP3 inflammasome and play a role in CKD, including extracellular matrix components biglycan, hyaluronan, and uric acid crystals.…”

Distinct cathepsins control necrotic cell death mediated by pyroptosis inducers and lysosome-destabilizing agents

“…For example, necrotic cell death has been linked to microbial pathogenesis, ischemic stroke, and induction of adaptive immune responses. 20,27,30,33,46,52 While most attention has focused on apoptotic cell death, recent evidence suggests that necrotic, like apoptotic cell death is a highly regulated process. 3,7,13,18,22,34 Unlike apoptotic cells, necrotic cells have a compromised plasma membrane, which leads to the leakage of cellular components, such as uric acid, HMGB1, DNA and ATP, into the extracellular media.…”