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

TLDR

Cytoplasmic innate immune receptors, notably the Nlrp3 inflammasome, sense cellular stress signals, oligomerize with ASC, activate caspase‑1, and trigger maturation of IL‑1β and IL‑18, making them therapeutic targets for diseases driven by excessive proinflammatory cytokines. The study aimed to determine whether the Nlrp3 inflammasome and its downstream effectors caspase‑1, IL‑1β, and IL‑18 contribute to renal ischemia‑reperfusion injury by comparing WT, Nlrp3‑/‑, and Asc‑/‑ mice. Using Nlrp3‑/‑ and Asc‑/‑ knockout mice, the authors evaluated renal injury after ischemia‑reperfusion and measured expression of caspase‑1, IL‑1β, and IL‑18 to assess inflammasome involvement. Loss of Nlrp3, but not Asc or its downstream cytokines, markedly protected mice from renal ischemia‑reperfusion injury, indicating a direct, inflammasome‑independent role of Nlrp3 in tubular epithelial cells.

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.