An inflammasome-independent role for epithelial-expressed Nlrp3 in renal ischemia-reperfusion injury.
An inflammasome-independent role for epithelial-expressed Nlrp3 in renal ischemia-reperfusion injury.
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DOI：
10.4049/jimmunol.1002330
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发表时间：
2010-11-15
期刊：
影响因子：
--
通讯作者：
McKay DB
中科院分区：
文献类型：
--
作者：
Shigeoka AA;Mueller JL;Kambo A;Mathison JC;King AJ;Hall WF;Correia Jda S;Ulevitch RJ;Hoffman HM;McKay DB
细胞质先天免疫受体是与促炎细胞因子过度产生相关疾病的重要治疗靶点。一种细胞质受体复合物Nlrp3炎性体对一系列与细胞应激相关的分子作出反应。在正常情况下，Nlrp3是自我抑制的，但在其配体存在的情况下，它寡聚，招募Asc，并触发caspase 1激活和促炎细胞因子如IL-1β和IL-18的成熟。由于缺血组织损伤是Nlrp3配体的潜在来源，我们的研究比较了野生型小鼠和Nlrp3炎性体成分缺乏小鼠（Nlrp3 - / -和Asc - / -小鼠）肾缺血的影响。为了研究炎症小体在肾IRI中的作用，我们还测试了其下游靶标caspase 1、IL-1 β和IL-18。Nlrp3和Asc在人和小鼠肾小管上皮中均高表达，缺乏Nlrp3，而不缺乏Asc或下游炎性小体靶点，可显著保护肾脏免受缺血再灌注损伤。我们得出结论，Nlrp3通过直接作用于肾小管上皮而导致肾缺血再灌注损伤，并且这种作用不依赖于炎性小体诱导的促炎细胞因子的产生。
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 auto-repressed but in the presence of its ligands, it oligomerizes, recruits Asc, and triggers caspase 1 activation and the maturation of proinflammatory cytokines such as IL-1β and IL-18. Since 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 IRI we also tested its downstream targets caspase 1, IL-1 β 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 ischemia reperfusion injury. We conclude that Nlrp3 contributes to renal ischemia reperfusion injury by a direct effect on renal tubular epithelium and that this effect is independent of inflammasome-induced proinflammatory cytokine production.
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DOI：
10.1097/01.asn.0000067652.51441.21
发表时间：
2003-06-01
影响因子：
13.6
作者：
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发表时间：
2005-12-16
影响因子：
3.1
作者：
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