An Inflammasome-Independent Role for Epithelial-Expressed Nlrp3 in Renal Ischemia-Reperfusion Injury

Abstract

Cytoplasmic innate immune receptors are important therapeutic targets for diseases associated with overproduction of proinflammatory cytokines. One cytoplasmic receptor complex, the Nlrp3 inflammasome, responds to an extensive array of molecules associated with cellular stress. Under normal conditions, Nlrp3 is autorepressed, but in the presence of its ligands, it oligomerizes, recruits apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc), and triggers caspase 1 activation and the maturation of proinflammatory cytokines such as IL-1β and IL-18. Because ischemic tissue injury provides a potential source for Nlrp3 ligands, our study compared and contrasted the effects of renal ischemia in wild-type mice and mice deficient in components of the Nlrp3 inflammasome (Nlrp3−/− and Asc−/− mice). To examine the role of the inflammasome in renal ischemia-reperfusion injury (IRI) we also tested its downstream targets caspase 1, IL-1β, and IL-18. Both Nlrp3 and Asc were highly expressed in renal tubular epithelium of humans and mice, and the absence of Nlrp3, but not Asc or the downstream inflammasome targets, dramatically protected from kidney IRI. We conclude that Nlrp3 contributes to renal IRI by a direct effect on renal tubular epithelium and that this effect is independent of inflammasome-induced proinflammatory cytokine production.

NLRP3 Inflammasome as a Novel Player in Myocardial Infarction

“…In the study by Sandanger, et al, 33) myocardial dysfunction and injury in response to I/R was signifi cantly improved in ex vivo Langendorff-perfused hearts isolated from NLRP3-KO mice compared with hearts isolated from wild-type and ASC-KO mice, suggesting different roles of NLRP3 and ASC in terms of myocardial damage after I/R. Similarly, Shigeoka, et al 34) showed that renal I/R injury was reduced in NLRP3-KO mice, but not in ASC-KO mice, and concluded that NLRP3 contributes to the development of renal I/R injury independent of the infl ammasome. We have also recently observed that hepatic I/ R injury was significantly ameliorated in NLRP3-KO mice, but not in ASC-KO mice.…”

Of Inflammasomes and Alarmins: IL-1β and IL-1α in Kidney Disease

“…21,75 However, postischemic tubular necrosis depends on NLRP3 [76][77][78][79] but not on ASC. 76 This finding could imply an additional, inflammasome-independent, biologic effect of ASC in postischemic AKI. Studies performed on the model of acute oxalosis suggest inflammasome signaling to be restricted to intrarenal dendritic cells.…”

NLRP3 regulates a non-canonical platform for caspase-8 activation during epithelial cell apoptosis

“…3,[19][20][21] We and others have demonstrated primarily non-canonical and inflammasome-independent roles for NLRP3 in the kidney epithelium and during experimental kidney injury in vivo. [20][21][22][23] For example, Nlrp3 − / − mice undergoing renal ischemia/reperfusion or unilateral ureteric obstruction (UUO) display reduced epithelial apoptosis and tubular injury independent of a canonical inflammasome or caspase-1. [20][21][22][23] In the intestinal tract, non-canonical NLRP3 regulates IL-18 maturation as well as epithelial cell shedding in response to Salmonella infection.…”

“…[20][21][22][23] For example, Nlrp3 − / − mice undergoing renal ischemia/reperfusion or unilateral ureteric obstruction (UUO) display reduced epithelial apoptosis and tubular injury independent of a canonical inflammasome or caspase-1. [20][21][22][23] In the intestinal tract, non-canonical NLRP3 regulates IL-18 maturation as well as epithelial cell shedding in response to Salmonella infection. 3 Despite these studies, the biology of NLRP3 and other inflammasomerelated genes in epithelial cells has yet to be fully elucidated.…”