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

Shigeoka, Alana A.; Mueller, James L.; Kambo, Amanpreet; Mathison, John C.; King, Andrew J.; Hall, Wesley F.; Correia, Jean da Silva; Ulevitch, Richard J.; Hoffman, Hal M.; McKay, Dianne B.

doi:10.4049/jimmunol.1002330

Cited by 217 publications

(240 citation statements)

References 62 publications

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“…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.…”

Section: Nlrp3 Inflammasome and Myocardial Infarction (Mi)mentioning

confidence: 96%

NLRP3 Inflammasome as a Novel Player in Myocardial Infarction

2014

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SummaryInfl ammasomes are multiple protein complexes that serve as molecular platforms to activate caspase-1 and regulate maturation of a potent proinfl ammatory cytokine, interleukin (IL)-1β, as well as proinfl ammatory cell death, pyroptosis. Although several types of infl ammasomes have been reported so far, recent investigations indicate that the NLRP3 infl ammasome recognizes non-microbial danger signals and leads to sterile infl ammatory responses in various disease conditions. Sterile infl ammatory responses are also implicated in the development of myocardial infarction (MI). In particular, IL-1β is an early and prominent mediator of infl ammatory responses in MI, suggesting the pathophysiologic role of NLRP3 infl ammasomes in MI. This review highlights the current state of knowledge regarding the role of NLRP3 infl ammasomes in MI. (Int Heart J 2014; 55: 101-105)

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Section: Nlrp3 Inflammasome and Myocardial Infarction (Mi)mentioning

confidence: 96%

NLRP3 Inflammasome as a Novel Player in Myocardial Infarction

2014

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“…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.…”

Section: Aki Modelsmentioning

confidence: 99%

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

Anders

2016

JASN

209

152

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Kidney injury implies danger signaling and a response by the immune system. The inflammasome is a central danger recognition platform that triggers local and systemic inflammation. In immune cells, inflammasome activation causes the release of mature IL-1b and of the alarmin IL-1a. Dying cells release IL-1a also, independently of the inflammasome. Both IL-1a and IL-1b ligate the same IL-1 receptor (IL-1R) that is present on nearly all cells inside and outside the kidney, further amplifying cytokine and chemokine release. Thus, the inflammasome-IL-1a/IL-b-IL-1R system is a central element of kidney inflammation and the systemic consequences. Seminal discoveries of recent years have expanded this central paradigm of inflammation. This review gives an overview of arising concepts of inflammasome and IL-1a/b regulation in renal cells and in experimental kidney disease models. There is a pipeline of compounds that can interfere with the inflammasome-IL-1a/IL-b-IL-1R system, ranging from recently described small molecule inhibitors of NLRP3, a component of the inflammasome complex, to regulatory agency-approved IL-1-neutralizing biologic drugs. Based on strong theoretic and experimental rationale, the potential therapeutic benefits of using such compounds to block the inflammasome-IL-1a/IL-b-IL-1R system in kidney disease should be further explored.

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“…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.…”

mentioning

confidence: 99%

“…[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.…”

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confidence: 99%

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

et al. 2016

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Nod-like receptor, pyrin containing 3 (NLRP3) is characterized primarily as a canonical caspase-1 activating inflammasome in macrophages. NLRP3 is also expressed in the epithelium of the kidney and gut; however, its function remains largely undefined. Primary mouse tubular epithelial cells (TEC) lacking Nlrp3 displayed reduced apoptosis downstream of the tumor necrosis factor (TNF) receptor and CD95. TECs were identified as type II apoptotic cells that activated caspase-8, tBid and mitochondrial apoptosis via caspase-9, responses that were reduced in Nlrp3 − / − cells. The activation of caspase-8 during extrinsic apoptosis induced by TNFα/cycloheximide (TNFα/CHX) was dependent on adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) and completely independent of caspase-1 or caspase-11. TECs and primary human proximal tubular epithelial cells (HPTC) did not activate a canonical inflammasome, caspase-1, or IL-1β secretion in response to TNFα/CHX or NLRP3-dependent triggers, such as ATP or nigericin. In cell fractionation studies and by confocal microscopy, NLRP3 colocalized with ASC and caspase-8 in speck-like complexes at the mitochondria during apoptosis. The formation of NLRP3/ASC/caspase-8 specks in response to TNFα/ CHX was downstream of TNFR signaling and dependent on potassium efflux. Epithelial ASC specks were present in enteroids undergoing apoptosis and in the injured tubules of wild-type but not Nlrp3 − / − or ASC − / − mice following ureteric unilateral obstruction in vivo. These data show that NLRP3 and ASC form a conserved non-canonical platform for caspase-8 activation, independent of the inflammasome that regulates apoptosis within epithelial cells.

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

Cited by 217 publications

References 62 publications

NLRP3 Inflammasome as a Novel Player in Myocardial Infarction

NLRP3 Inflammasome as a Novel Player in Myocardial Infarction

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

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

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