Interleukin-22 ameliorated renal injury and fibrosis in diabetic nephropathy through inhibition of NLRP3 inflammasome activation.
Interleukin-22 ameliorated renal injury and fibrosis in diabetic nephropathy through inhibition of NLRP3 inflammasome activation.
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Interleukin-22 通过抑制 NLRP3 炎性体激活改善糖尿病肾病的肾损伤和纤维化
DOI：
10.1038/cddis.2017.292
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发表时间：
2017-07-20
影响因子：
9
通讯作者：
Ju D
中科院分区：
文献类型：
--
作者：
Wang S;Li Y;Fan J;Zhang X;Luan J;Bian Q;Ding T;Wang Y;Wang Z;Song P;Cui D;Mei X;Ju D
糖尿病肾病（diabetic nephropathy，DN）是糖尿病最致命的并发症之一，伴有代谢紊乱和慢性炎症反应。虽然细胞因子IL-22最初与慢性炎症性疾病的发病机制有关，但最近的研究表明IL-22可以抑制炎症反应并减轻组织损伤。在此，我们研究了IL-22在DN中的作用。我们发现DN患者和小鼠血清IL-22水平均显著下调。IL-22表达随DN进展而进一步下降，而IL-22基因治疗显著改善了已建立的肾病小鼠的肾损伤和系膜基质扩张。IL-22还能剂量依赖性地降低高糖和TGF-β1诱导的小鼠肾小球系膜细胞FN和胶原IV的过度表达，提示IL-22在体外可能具有抑制ECM过度表达的作用。同时，IL-22基因治疗显著减轻了DN的肾纤维化和蛋白尿排泄。此外，IL-22基因治疗显着减弱高血糖和代谢紊乱的链脲佐菌素诱导的实验性糖尿病小鼠。值得注意的是，IL-22显著逆转了DN中NLRP 3的肾活化、半胱天冬酶-1的切割和IL-1β的成熟，表明IL-22通过抑制体内NLRP 3炎性体的活化而具有意想不到的抗炎功能。此外，IL-22以剂量依赖性方式显著下调高糖诱导的肾系膜细胞中NLRP 3炎性小体的活化，表明IL-22对NLRP 3炎性小体活化的作用不依赖于改善的血糖控制。这些结果表明，DN中IL-22的肾保护作用最可能与NLRP 3炎性体的活化减少有关。结论：IL-22可通过下调肾脏NLRP 3/caspase-1/IL-1β信号通路，减轻DN患者的全身代谢综合征，对DN具有治疗作用。
Diabetic nephropathy (DN) is one of the most lethal complications of diabetes mellitus with metabolic disorders and chronic inflammation. Although the cytokine IL-22 was initially implicated in the pathogenesis of chronic inflammatory diseases, recent studies suggested that IL-22 could suppress inflammatory responses and alleviate tissue injury. Herein, we examined the role of IL-22 in DN. We found that serum levels of IL-22 were significantly downregulated in both patients and mice with DN. The expression of IL-22 was further decreased with the progression of DN, whereas IL-22 gene therapy significantly ameliorated renal injury and mesangial matrix expansion in mice with established nephropathy. IL-22 could also markedly reduce high glucose-induced and TGF-β1-induced overexpression of fibronectin and collagen IV in mouse renal glomerular mesangial cells in a dose-dependent manner, suggesting the potential role of IL-22 to inhibit the overproduction of ECM in vitro. Simultaneously, IL-22 gene therapy drastically alleviated renal fibrosis and proteinuria excretion in DN. In addition, IL-22 gene therapy markedly attenuated hyperglycemia and metabolic disorders in streptozotocin-induced experimental diabetic mice. Notably, IL-22 drastically reversed renal activation of NLRP3, cleavage of caspase-1, and the maturation of IL-1β in DN, suggesting unexpected anti-inflammatory function of IL-22 via suppressing the activation of NLRP3 inflammasome in vivo. Moreover, IL-22 markedly downregulated high glucose-induced activation of NLRP3 inflammasome in renal mesangial cells in a dose-dependent manner, indicating that the effects of IL-22 on NLRP3 inflammasome activation was independent of improved glycemic control. These results suggested that nephroprotection by IL-22 in DN was most likely associated with reduced activation of NLRP3 inflammasome. In conclusion, our finding demonstrated that IL-22 could exert favorable effects on DN via simultaneously alleviating systemic metabolic syndrome and downregulating renal NLRP3/caspase-1/IL-1β pathway, suggesting that IL-22 might have therapeutic potential for the treatment of DN.
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影响因子：
16
作者：
Martinon, F;Burns, K;Tschopp, J
通讯作者：
Tschopp, J
影响因子：
32.4
作者：
Agostini, L;Martinon, F;Tschopp, J
通讯作者：
Tschopp, J
影响因子：
29.4
作者：
Andoh, A;Zhang, ZB;Fujiyama, Y
通讯作者：
Fujiyama, Y
影响因子：
13.6
作者：
Ortiz-Munoz, Guadalupe;Lopez-Parra, Virginia;Gomez-Guerrero, Carmen
通讯作者：
Gomez-Guerrero, Carmen
影响因子：
5
作者：
Li, Yubin;Zeng, Xian;Ju, Dianwen
通讯作者：
Ju, Dianwen