Negative regulatory responses to metabolically triggered inflammation impair renal epithelial immunity in diabetes mellitus.
Negative regulatory responses to metabolically triggered inflammation impair renal epithelial immunity in diabetes mellitus.
复制标题
对代谢触发的炎症的负调节反应会损害糖尿病中的肾上皮免疫。
DOI：
10.1007/s00109-012-0969-x
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发表时间：
2013-05
影响因子：
4.7
通讯作者：
Kon, Oi Lian
中科院分区：
文献类型：
--
作者：
Chen, Nelson K. F.;Chong, Tsung Wen;Loh, Hwai-Liang;Lim, Kiat Hon;Gan, Valerie H. L.;Wang, Marian;Kon, Oi Lian
关键词：
糖尿病的特征是慢性炎症和感染风险增加，尤其是暴露于外部环境的组织。然而，影响免疫细胞及其在糖尿病中的功能的因果分子机制尚不清楚。在这里，我们通过转录和蛋白质分析显示，与非糖尿病对照相比，糖尿病肾脏中葡萄糖诱导的组织损伤、慢性炎症、氧化应激以及多种炎症和免疫相关分子表达失调的特征。涉及细胞因子、G 蛋白偶联受体、蛋白激酶 C 亚型、丝裂原激活蛋白激酶、核因子 κB (NFκB) 和 Toll 样受体 (TLR) 的异常信号传导是显而易见的。这些伴随着 NFκB、TLR 和其他促炎通路负调节因子的过度表达，例如 A20、SOCS1、IRAK-M、IκBα、Triad3A、Tollip、SIGIRR 和 ST2L。有利于 TH2 反应的抗炎和免疫调节分子，例如 IL-10、IL-4 和 TSLP 被强烈诱导。这些免疫功能障碍的分子指标使我们在糖尿病受试者三分之一以上的肾脏中检测到细菌和人类巨细胞病毒的隐秘存在，但在非糖尿病患者的肾脏中则没有。在暴露于高葡萄糖、促炎细胞因子和甲基乙二醛的原代人肾小管上皮（但不是系膜）细胞培养物中可以诱导类似的信号传导异常，并且通过抗氧化剂和 PKC 抑制剂的联合药物治疗可以逆转。我们的研究结果表明，糖尿病会损害上皮免疫，这是反调节免疫反应长期且不适当激活的结果，而反调节免疫反应是针对炎症的生理保护机制。这里描述的免疫异常和隐匿性肾脏感染可能会导致糖尿病肾病的进展。本文的在线版本 (doi:10.1007/s00109-012-0969-x) 包含补充材料，可供授权用户使用。
Diabetes mellitus is characterized by chronic inflammation and increased risk of infections, particularly of tissues exposed to the external environment. However, the causal molecular mechanisms that affect immune cells and their functions in diabetes are unclear. Here we show, by transcript and protein analyses, signatures of glucose-induced tissue damage, chronic inflammation, oxidative stress, and dysregulated expression of multiple inflammation- and immunity-related molecules in diabetic kidneys compared with non-diabetic controls. Abnormal signaling involving cytokines, G-protein coupled receptors, protein kinase C isoforms, mitogen-activated protein kinases, nuclear factor-κB (NFκB), and Toll-like receptors (TLR) were evident. These were accompanied by overexpression of negative regulators of NFκB, TLR, and other proinflammatory pathways, e.g., A20, SOCS1, IRAK-M, IκBα, Triad3A, Tollip, SIGIRR, and ST2L. Anti-inflammatory and immunomodulatory molecules, e.g., IL-10, IL-4, and TSLP that favor TH2 responses were strongly induced. These molecular indicators of immune dysfunction led us to detect the cryptic presence of bacteria and human cytomegalovirus in more than one third of kidneys of diabetic subjects but none in non-diabetic kidneys. Similar signaling abnormalities could be induced in primary human renal tubular epithelial (but not mesangial) cell cultures exposed to high glucose, proinflammatory cytokines and methylglyoxal, and were reversed by combined pharmacological treatment with an antioxidant and a PKC inhibitor. Our results suggest that diabetes impairs epithelial immunity as a consequence of chronic and inappropriate activation of counter-regulatory immune responses, which are otherwise physiological protective mechanisms against inflammation. The immune abnormalities and cryptic renal infections described here may contribute to progression of diabetic nephropathy. The online version of this article (doi:10.1007/s00109-012-0969-x) contains supplementary material, which is available to authorized users.
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影响因子：
6.7
作者：
Dolowschiak T;Chassin C;Ben Mkaddem S;Fuchs TM;Weiss S;Vandewalle A;Hornef MW
通讯作者：
Hornef MW
影响因子：
--
作者：
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通讯作者：
Hoepelman, AIM
影响因子：
4.8
作者：
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通讯作者：
Strauss, JF
影响因子：
15.9
作者：
Schaefer, L;Babelova, A;Gröne, HJ
通讯作者：
Gröne, HJ
影响因子：
7.7
作者：
Secrest, Aaron M.;Becker, Dorothy J.;Orchard, Trevor J.
通讯作者：
Orchard, Trevor J.