Department of Internal Medicine I, University Hospital, Goethe University, Frankfurt, Germany.
Department of Internal Medicine I, University of Bonn, Bonn, Germany.
Front Immunol. 2020 Jul 7;11:1352. doi: 10.3389/fimmu.2020.01352. eCollection 2020.
The macrophage-inducible C-type lectin (mincle) is part of the innate immune system and acts as a pattern recognition receptor for pathogen-associated molecular patterns (PAMPS) and damage-associated molecular patterns (DAMPs). Ligand binding induces mincle activation which consequently interacts with the signaling adapter Fc receptor, SYK, and NF-kappa-B. There is also evidence that mincle expressed on macrophages promotes intestinal barrier integrity. However, little is known about the role of mincle in hepatic fibrosis, especially in more advanced disease stages. Mincle expression was measured in human liver samples from cirrhotic patients and donors collected at liver transplantation and in patients undergoing bariatric surgery. Human results were confirmed in rodent models of cirrhosis and acute-on-chronic liver failure (ACLF). In these models, the role of mincle was investigated in liver samples as well as in peripheral blood monocytes (PBMC), tissues from the kidney, spleen, small intestine, and heart. Additionally, mincle activation was stimulated in experimental non-alcoholic steatohepatitis (NASH) by treatment with mincle agonist trehalose-6,6-dibehenate (TDB). In human NASH, mincle is upregulated with increased collagen production. In ApoE deficient mice fed high-fat western diet (NASH model), mincle activation significantly increases hepatic collagen production. In human cirrhosis, mincle expression is also significantly upregulated. Furthermore, mincle expression is associated with the stage of chronic liver disease. This could be confirmed in rat models of cirrhosis and ACLF. ACLF was induced by LPS injection in cirrhotic rats. While mincle expression and downstream signaling via FC receptor gamma, SYK, and NF-kappa-B are upregulated in the liver, they are downregulated in PBMCs of these rats. Although mincle expressed on macrophages might be beneficial for intestinal barrier integrity, it seems to contribute to inflammation and fibrosis once the intestinal barrier becomes leaky in advanced stages of chronic liver disease.
巨噬细胞诱导 C 型凝集素 (mincle) 是先天免疫系统的一部分，作为病原体相关分子模式 (PAMPs) 和损伤相关分子模式 (DAMPs) 的模式识别受体发挥作用。配体结合诱导 mincle 激活，随后与信号适配器 Fc 受体、SYK 和 NF-κB 相互作用。有证据表明，巨噬细胞表达的 mincle 促进肠道屏障完整性。然而，关于 mincle 在肝纤维化中的作用知之甚少，特别是在更晚期的疾病阶段。在肝硬化患者和肝移植时采集的供体的人肝组织样本以及接受减肥手术的患者中测量了 mincle 的表达。在肝硬化和慢性肝衰竭急性加重 (ACLF) 的啮齿动物模型中证实了人类的结果。在这些模型中，在肝组织以及外周血单核细胞 (PBMC)、肾脏、脾脏、小肠和心脏组织中研究了 mincle 的作用。此外，通过用 mincle 激动剂海藻糖-6,6-二硬脂酸酯 (TDB) 处理实验性非酒精性脂肪性肝炎 (NASH) 来刺激 mincle 激活。在人类 NASH 中，mincle 上调伴有胶原产生增加。在高脂西方饮食喂养的 ApoE 缺陷小鼠 (NASH 模型) 中，mincle 激活显著增加肝胶原产生。在人类肝硬化中，mincle 表达也显著上调。此外，mincle 表达与慢性肝病的阶段相关。这在肝硬化和 ACLF 的大鼠模型中得到了证实。通过 LPS 注射在肝硬化大鼠中诱导 ACLF。虽然在肝脏中 mincle 表达和通过 FC 受体 γ、SYK 和 NF-κB 的下游信号转导上调，但在这些大鼠的 PBMC 中下调。尽管在肠道屏障在慢性肝病的晚期变得渗漏时，巨噬细胞上表达的 mincle 可能对肠道屏障完整性有益，但它似乎有助于炎症和纤维化。
