Environmental Health and Disease Laboratory, Departments of Environmental Health Sciences, University of South Carolina, Columbia, SC 29208, USA.
Free Radical Research Center, Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI, USA.
Redox Biol. 2017 Oct;13:8-19. doi: 10.1016/j.redox.2017.05.005. Epub 2017 May 10.
Recent clinical studies found a strong association of colonic inflammation and Inflammatory bowel disease (IBD)-like phenotype with NonAlcoholic Fatty liver Disease (NAFLD) yet the mechanisms remain unknown. The present study identifies high mobility group box 1 (HMGB1) as a key mediator of intestinal inflammation in NAFLD and outlines a detailed redox signaling mechanism for such a pathway. NAFLD mice showed liver damage and release of elevated HMGB1 in systemic circulation and increased intestinal tyrosine nitration that was dependent on NADPH oxidase. Intestines from NAFLD mice showed higher Toll like receptor 4 (TLR4) activation and proinflammatory cytokine release, an outcome strongly dependent on the existence of NAFLD pathology and NADPH oxidase. Mechanistically intestinal epithelial cells showed the HMGB1 activation of TLR-4 was both NADPH oxidase and peroxynitrite dependent with the latter being formed by the activation of NADPH oxidase. Proinflammatory cytokine production was significantly blocked by the specific peroxynitrite scavenger phenyl boronic acid (FBA), AKT inhibition and NADPH oxidase inhibitor Apocynin suggesting NADPH oxidase-dependent peroxynitrite is a key mediator in TLR-4 activation and cytokine release via an AKT dependent pathway. Studies to ascertain the mechanism of HMGB1-mediated NADPH oxidase activation showed a distinct role of Receptor for advanced glycation end products (RAGE) as the use of inhibitors targeted against RAGE or use of deformed HMGB1 protein prevented NADPH oxidase activation, peroxynitrite formation, TLR4 activation and finally cytokine release. Thus, in conclusion the present study identifies a novel role of HMGB1 mediated inflammatory pathway that is RAGE and redox signaling dependent and helps promote ectopic intestinal inflammation in NAFLD.
最近的临床研究发现，结直肠炎症和炎症性肠病（IBD）样表型与非酒精性脂肪性肝病（NAFLD）之间存在很强的关联，但机制尚不清楚。本研究确定高迁移率族蛋白 B1（HMGB1）是 NAFLD 中肠道炎症的关键介质，并概述了这种途径的详细氧化还原信号机制。NAFLD 小鼠表现出肝损伤和系统循环中 HMGB1 水平升高，以及依赖 NADPH 氧化酶的肠道酪氨酸硝化增加。NAFLD 小鼠的肠道表现出更高的 Toll 样受体 4（TLR4）激活和促炎细胞因子释放，这种结果强烈依赖于 NAFLD 病理学和 NADPH 氧化酶的存在。从机制上讲，肠道上皮细胞显示 HMGB1 激活 TLR-4 既依赖于 NADPH 氧化酶，也依赖于过氧亚硝酸盐，而过氧亚硝酸盐是由 NADPH 氧化酶的激活形成的。特异性过氧亚硝酸盐清除剂苯硼酸（FBA）、AKT 抑制和 NADPH 氧化酶抑制剂 Apocynin 显著阻断了促炎细胞因子的产生，这表明 NADPH 氧化酶依赖性过氧亚硝酸盐是 TLR-4 激活和通过 AKT 依赖途径释放细胞因子的关键介质。为确定 HMGB1 介导的 NADPH 氧化酶激活的机制而进行的研究表明，晚期糖基化终产物受体（RAGE）具有独特的作用，因为使用针对 RAGE 的抑制剂或使用变形的 HMGB1 蛋白可防止 NADPH 氧化酶激活、过氧亚硝酸盐形成、TLR4 激活和最终细胞因子释放。因此，综上所述，本研究确定了 HMGB1 介导的炎症途径的新作用，该途径依赖于 RAGE 和氧化还原信号，有助于促进 NAFLD 中的异位肠道炎症。
