HIV Promotes NLRP3 Inflammasome Complex Activation in Murine HIV-Associated Nephropathy
HIV Promotes NLRP3 Inflammasome Complex Activation in Murine HIV-Associated Nephropathy
复制标题
艾滋病毒促进小鼠艾滋病毒相关肾病中 NLRP3 炎症小体复合物的活化
DOI：
10.1016/j.ajpath.2015.10.002
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发表时间：
2016-02-01
影响因子：
6
通讯作者：
Singhal, Pravin C.
中科院分区：
文献类型：
--
作者：
Haque, Shabirul;Lan, Xiqian;Singhal, Pravin C.
足细胞的生长失调和丢失是HIV相关肾病的重要特征。近年来，HIV通过诱导Nod样受体蛋白3（Nod-like receptor protein 3，NLRP 3）炎性小体复合物，在T淋巴细胞中诱导一种新的程序性细胞死亡--细胞凋亡。我们在体内和体外评估了HIV在足细胞NLRP 3炎性小体形成中的作用。HIV转基因小鼠（Tg 26）的肾皮质切片显示NLRP 3、ASC（CARD蛋白）、半胱天冬酶-1和IL-11蛋白的表达增加，证实了Tg 26小鼠足细胞中NLRP 3炎性体复合物的形成。Tg 26小鼠的肾组织还显示炎性体标志物（NLRP 3、ASC和半胱天冬酶-1和IL-113）的mRNA水平和蛋白表达增强。与FVBN小鼠相比，Tg 26小鼠的血清还显示升高的IL-11细胞因子浓度。HIV在足细胞内以剂量和时间依赖性方式诱导细胞凋亡，这是炎性小体活化的表型。Caspase-1抑制剂不仅减弱了Caspase-1和IL-143的足细胞表达，而且还提供了对焦亡的保护，这表明HIV诱导的足细胞损伤是由Caspase-1激活介导的。有趣的是，HIV诱导的足细胞焦亡可以部分抑制Tempol（超氧化物歧化酶模拟剂）和格列本脲（钾外流抑制剂）。这些发现表明，活性氧和钾外流的产生有助于HIV诱导的足细胞焦亡和NLRP 3炎性小体激活。
Dysregulated growth and loss of podocytes are important features of HIV-associated nephropathy. Recently, HIV was reported to induce a new type of programed cell death, pyroptosis, in T lymphocytes through induction of Nod-like receptor protein3 (NLRP3) inflammasome complexes. We evaluated the role of HIV in podocyte NLRP3 inflammasome formation both in vivo and in vitro. Renal cortical sections of HIV-transgenic mice (Tg26) displayed increased expression of NLRP3, ASC (a CARD protein), caspase-1, and IL-ill proteins, confirming NLRP3 inflammasome complex formation in podocytes of Tg26 mice. Renal tissues of Tg26 mice also displayed enhanced mRNA levels and protein expressions of inflammasome markers (NLRP3, ASC, and caspase-1, and IL-113). Serum of Tg26 mice also showed elevated concentrations of IL-ill cytokine compared with FVBN mice. HIV induced pyroptosis in a dose- and time-dependent manner within podocytes, a phenotype of inflammasome activation. Caspase-1 inhibitor not only attenuated podocyte expression of caspase-1 and IL-143 but also provided protection against pyroptosis, suggesting that HIV-induced podocyte injury was mediated by caspase-1 activation. Interestingly, HIV-induced podocyte pyroptosis could be partially inhibited by Tempol (a superoxide dismutase-mimetic agent) and by glyburide (an inhibitor of potassium efflux). These findings suggest that generation of reactive oxygen species and potassium efflux contribute to HIV-induced pyroptosis and NLRP3 inflammasome activation in podocytes.