Optineurin inhibits NLRP3 inflammasome activation by enhancing mitophagy of renal tubular cells in diabetic nephropathy
Optineurin inhibits NLRP3 inflammasome activation by enhancing mitophagy of renal tubular cells in diabetic nephropathy
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Optineurin 通过增强糖尿病肾病肾小管细胞的线粒体自噬抑制 NLRP3 炎症小体激活
DOI：
10.1096/fj.201801749rrr
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发表时间：
2019-03-01
期刊：
影响因子：
4.8
通讯作者：
He, Yani
中科院分区：
文献类型：
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作者：
Chen, Kehong;Feng, Lei;He, Yani
小管间质炎症在糖尿病肾病（DN）的进展中起关键作用，核苷酸结合寡聚化结构域样受体家族含pyrin结构域3 （NLRP3）炎症小体参与了DN的肾间质炎症。OPTN的表达减少也与DN的进展有关。我们研究了OPTN在DN中NLRP3炎性小体激活中的作用。我们初步检查了172例2型DN患者和32例非糖尿病肾错构瘤患者的肾活检组织。DN患者肾OPTN表达显著降低，且与尿IL-1、IL-18水平呈负相关。活检共聚焦显微镜分析显示，OPTN阳性肾小管上皮细胞（RTECs）未见NLRP3或IL-1染色，表明OPTN表达与NLRP3炎性体的激活呈负相关。小鼠RTECs的体外研究表明，高糖刺激后，OPTN mRNA和蛋白水平显著降低。与给予HG的RTECs相比，过表达OPTN的RTECs NLRP3表达水平、caspase-1和IL-1的裂解水平以及IL-1和IL-18的释放水平均显著降低。HG存在下，过表达OPTN显著增加RTECs中微管相关蛋白1A/ 1b -轻链3-II和线粒体外膜转座酶20的表达，表明OPTN促进了线粒体自噬。此外，在HG存在的情况下，线粒体分裂抑制剂1阻断了OPTN过表达对NLRP3炎性小体激活的抑制作用，说明OPTN过表达通过增强线粒体自噬抑制NLRP3炎性小体激活。与HG+OPTN小干扰RNA （siRNA）处理的RTECs相比，HG+OPTN siRNA+ mitotempo处理的RTECs减弱了NLRP3炎症小体的激活，这表明OPTN基因沉默通过增加HG处理的RTECs中的mtROS来激活NLRP3炎症小体。综上所述，我们的研究结果表明，OPTN通过增强线粒体自噬来抑制NLRP3炎性体的激活。K。陈,冯,L, W,陈,J。,,X。,,我,他,y Optineurin抑制NLRP3 inflammasome激活增强mitophagy糖尿病肾病的肾小管细胞。
Tubulointerstitial inflammation plays a critical role in the progression of diabetic nephropathy (DN), and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes contribute to renal interstitial inflammation in DN. Decreased expression of optineurin (OPTN) is also associated with the progression of DN. We investigated the role of OPTN in activation of the NLRP3 inflammasome in DN. We initially examined the renal biopsy tissues of 172 patients with type 2 DN and 32 nondiabetic patients with renal hamartoma. Expression of renal OPTN was significantly lower in patients with DN and negatively correlated with urinary levels of IL-1 and IL-18. Confocal microscopy analysis of the biopsies indicated no NLRP3 or IL-1 staining in OPTN-positive renal tubular epithelial cells (RTECs), indicating a negative correlation of OPTN expression with the activation of NLRP3 inflammasome. In vitro studies of murine RTECs indicated the levels of OPTN mRNA and protein decreased significantly after stimulation by a high glucose (HG) treatment. Relative to RTECs given HG, RTECs overexpressing OPTN showed significantly lower levels of NLRP3 expression, cleavage of caspase-1 and IL-1, and release of IL-1 and IL-18. Overexpression of OPTN in the presence of HG significantly increased the costaining of microtubule-associated protein 1A/1B-light chain 3-II and translocase of outer mitochondrial membrane 20 in RTECs, suggesting that OPTN enhances mitophagy. In addition, mitochondrial division inhibitor 1 blocked the inhibitory effect of OPTN overexpression on the activation of NLRP3 inflammasome in the presence of HG, indicating that OPTN overexpression inhibited NLRP3 inflammasome activation by enhancement of mitophagy. OPTN gene silencing significantly enhanced production of mitochondrial reactive oxygen species (mtROS) in the presence of HG. Compared with HG+OPTN small interfering RNA (siRNA)-treated RTECs, HG+OPTN siRNA+MitoTempo-treated RTECs attenuated NLRP3 inflammasome activation, suggesting that OPTN gene silencing activates the NLRP3 inflammasome by increasing mtROS in HG-treated RTECs. Taken together, our results demonstrate that OPTN inhibits the activation of NLRP3 inflammasome by enhancing mitophagy.Chen, K., Feng, L., Hu, W., Chen, J., Wang, X., Wang, L., He, Y. Optineurin inhibits NLRP3 inflammasome activation by enhancing mitophagy of renal tubular cells in diabetic nephropathy.