Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome

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-1␤. Necrotic cells produced by pressure disruption, hypoxic injury, or complementmediated 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.caspase-1 ͉ interleukin-1␤ ͉ necrosis

Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration

“…In other studies, it was shown that damaged mitochondria released from necrotic cells are critical for inflammatory responses to tissue injury. 47,48 These findings suggest that several DAMPs may contribute to inflammatory amplification in tissue degeneration and that preventing necrosis, which is the source of multiple DAMPs, may be a potential therapy to protect tissues against injury and excessive inflammation.…”

RAGE Does Not Contribute to Renal Injury and Damage upon Ischemia/Reperfusion-Induced Injury

“…HMGB1 can, however, also induce activation of intracellular signaling pathways via interaction with PRRs other than RAGE including: Toll-like receptor (TLR) 2, TLR-4 and inflammasome NACHT, LRR and PYD domains-containing protein 3 (Nlrp3) [32,33] . We and others have shown that ␣ HMGB1-treated WT mice, TLR2 KO, TLR4 KO and Nlrp3 KO mice display a similar phenotype following renal I/R [16,17,21,30,31,[34][35][36] . Together, these reports implicate that the deleterious effect of HMGB1 in the development of renal I/R injury is not mediated by RAGE signaling, but rather by TLRs and/or Nlrp3.…”

“…Renal I/R injury was induced as described previously [15][16][17] . Briefly, both renal arteries were clamped for 30 min under general anesthesia (0.07 ml/10 g mouse of fentanyl citrate fluanisone midazolam mixture containing: 1.25 mg/ml midazolam (Roche Diagnostics Corp.), 0.08 mg/ml fentanyl citrate, and 2.5 mg/ml fluanisone (Janssen Pharmaceutica)), which induces profound renal damage and dysfunction without inducing mortality [17] .…”

Activation of cell-surface proteases promotes necroptosis, inflammation and cell migration

“…To examine whether ADAM activation in necroptotic cells plays a role in necroptosis-triggered inflammatory responses, we first tested the effect of cell culture medium on macrophage activation in vitro and found that the medium of TSZ-treated wild-type, but not ADAM10/17 double knockout, MEFs induced much greater upregulation of IFN-γ, IL-6, TNF-α and VEGF expression in To test this possibility in vivo, we intraperitoneally injected TSZ-treated control or ADAM10/17 double knockout MEFs, cultured in suspension, into C57BL/6 mice. Sixteen hours after injection, mice injected with ADAM10/17 double knockout MEFs had much less neutrophils in their peritoneal cavity compared with mice injected with control cells, suggesting that the inflammatory responses triggered by ADAM10/17 double knockout cells were significantly lower [30,31] ( Figure 5C and 5D). To further evaluate the role of ADAM activation in necroptosis/inflammation in vivo, we analyzed the effect of ADAM inhibition in caerulein-induced pancreatitis mouse model and found that ADAM inhibition with GW280264X dramatically protected mice from pancreas acinar cell loss and necrosis ( Figure 5E).…”