Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13# Hangkong Road, Wuhan, 430030, China.
Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA.
Clin Exp Med. 2023 Oct;23(6):2167-2179. doi: 10.1007/s10238-022-00960-8. Epub 2022 Dec 1.
Activation of T cells and pro-inflammatory cytokines are essential for human autoimmune hepatitis. RAGE is one of the receptors for the inflammatory alarm molecule high mobility group box 1 (HMGB1), and it is involved in autoimmune hepatitis. However, the molecular mechanism of RAGE in the context of autoimmune hepatitis remains elusive. This study aimed to identify the function and mechanism of RAGE in autoimmune hepatitis. The role and underlying mechanisms of RAGE signaling-driven immune inflammatory response in ConA-induced experimental hepatitis were examined using the RAGE-deficient mice. We found that the RAGE deficiency protected the mouse from liver inflammatory injury caused by the ConA challenge. mRNA expression of VCAM-1, IL-6, and TNF-α within the livers is markedly decreased in RAGE-deficient mice compared to wild-type mice. In parallel, RAGE deficiency leads to reduced levels of the serum pro-inflammatory cytokines IL-6 and TNF-α as compared with wild-type control mice. RAGE-deficient mice exhibit increased hepatic NK cells and decreased CD4 T cells compared with wild-type control mice. Notably, in vivo blockade of IL-6 in wild-type mice significantly protected mice from ConA-induced hepatic injury. Furthermore, RAGE deficiency impaired IL-6 production and was associated with decreased expression of Arid5a in liver tissues, a half-life IL-6 mRNA regulator. RAGE signaling is important in regulating the development of autoimmune hepatitis. Immune regulation of RAGE may represent a novel therapeutic strategy to prevent immune-mediated liver injury.
T 细胞和促炎细胞因子的激活对于人类自身免疫性肝炎至关重要。RAGE 是炎症警报分子高迁移率族蛋白 B1 (HMGB1) 的受体之一，它与自身免疫性肝炎有关。然而，RAGE 在自身免疫性肝炎中的分子机制仍不清楚。本研究旨在确定 RAGE 在自身免疫性肝炎中的功能和机制。使用 RAGE 缺陷小鼠研究了 RAGE 信号驱动的免疫炎症反应在 ConA 诱导的实验性肝炎中的作用和潜在机制。我们发现 RAGE 缺乏可保护小鼠免受 ConA 攻击引起的肝脏炎症损伤。与野生型小鼠相比，RAGE 缺陷小鼠肝脏中 VCAM-1、IL-6 和 TNF-α 的 mRNA 表达明显降低。平行地，与野生型对照小鼠相比，RAGE 缺陷小鼠的血清促炎细胞因子 IL-6 和 TNF-α 水平降低。与野生型对照小鼠相比，RAGE 缺陷小鼠的肝脏 NK 细胞增加，CD4 T 细胞减少。值得注意的是，体内阻断野生型小鼠的 IL-6 可显著保护小鼠免受 ConA 诱导的肝损伤。此外，RAGE 缺陷会损害 IL-6 的产生，并与肝组织中 Arid5a 的表达减少相关，Arid5a 是一种 IL-6 mRNA 调节剂的半衰期。RAGE 信号在调节自身免疫性肝炎的发展中很重要。RAGE 的免疫调节可能代表一种预防免疫介导的肝损伤的新治疗策略。
