Weiskirchen Ralf, Tacke Frank
1 Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, 2 Department of Internal Medicine III, RWTH University Hospital Aachen, Aachen, Germany.
Hepatobiliary Surg Nutr. 2014 Dec;3(6):344-63. doi: 10.3978/j.issn.2304-3881.2014.11.03.
The liver is a central immunological organ. Liver resident macrophages, Kupffer cells (KC), but also sinusoidal endothelial cells, dendritic cells (DC) and other immune cells are involved in balancing immunity and tolerance against pathogens, commensals or food antigens. Hepatic stellate cells (HSCs) have been primarily characterized as the main effector cells in liver fibrosis, due to their capacity to transdifferentiate into collagen-producing myofibroblasts (MFB). More recent studies elucidated the fundamental role of HSC in liver immunology. HSC are not only the major storage site for dietary vitamin A (Vit A) (retinol, retinoic acid), which is essential for proper function of the immune system. This pericyte further represents a versatile source of many soluble immunological active factors including cytokines [e.g., interleukin 17 (IL-17)] and chemokines [C-C motif chemokine (ligand) 2 (CCL2)], may act as an antigen presenting cell (APC), and has autophagy activity. Additionally, it responds to many immunological triggers via toll-like receptors (TLR) (e.g., TLR4, TLR9) and transduces signals through pathways and mediators traditionally found in immune cells, including the Hedgehog (Hh) pathway or inflammasome activation. Overall, HSC promote rather immune-suppressive responses in homeostasis, like induction of regulatory T cells (Treg), T cell apoptosis (via B7-H1, PDL-1) or inhibition of cytotoxic CD8 T cells. In conditions of liver injury, HSC are important sensors of altered tissue integrity and initiators of innate immune cell activation. Vice versa, several immune cell subtypes interact directly or via soluble mediators with HSC. Such interactions include the mutual activation of HSC (towards MFB) and macrophages or pro-apoptotic signals from natural killer (NK), natural killer T (NKT) and gamma-delta T cells (γδ T-cells) on activated HSC. Current directions of research investigate the immune-modulating functions of HSC in the environment of liver tumors, cellular heterogeneity or interactions promoting HSC deactivation during resolution of liver fibrosis. Understanding the role of HSC as central regulators of liver immunology may lead to novel therapeutic strategies for chronic liver diseases.
肝脏是一个重要的免疫器官。肝脏驻留巨噬细胞，即库普弗细胞（KC），以及窦状内皮细胞、树突状细胞（DC）和其他免疫细胞，都参与了对病原体、共生菌或食物抗原的免疫平衡和耐受性调节。肝星状细胞（HSC）主要被认为是肝纤维化的主要效应细胞，因为它们能够转分化为产生胶原蛋白的肌成纤维细胞（MFB）。最近的研究阐明了HSC在肝脏免疫学中的重要作用。HSC不仅是膳食维生素A（维生素A）（视黄醇、视黄酸）的主要储存部位，而维生素A对免疫系统的正常功能至关重要。这种周细胞还是许多可溶性免疫活性因子的多功能来源，包括细胞因子[如白细胞介素-17（IL-17）]和趋化因子[C-C基序趋化因子（配体）2（CCL2）]，可能作为抗原呈递细胞（APC），并具有自噬活性。此外，它通过Toll样受体（TLR）（如TLR4、TLR9）对许多免疫触发因素作出反应，并通过传统上在免疫细胞中发现的信号通路和介质转导信号，包括刺猬（Hh）通路或炎性小体激活。总体而言，HSC在稳态中促进免疫抑制反应，如诱导调节性T细胞（Treg）、T细胞凋亡（通过B7-H1、PDL-1）或抑制细胞毒性CD8 T细胞。在肝损伤情况下，HSC是组织完整性改变的重要传感器和先天免疫细胞激活的启动者。反之，几种免疫细胞亚型直接或通过可溶性介质与HSC相互作用。这种相互作用包括HSC（向MFB）与巨噬细胞的相互激活，或自然杀伤（NK）、自然杀伤T（NKT）和γδ T细胞（γδ T细胞）对活化HSC的促凋亡信号。当前的研究方向是探讨HSC在肝肿瘤环境、细胞异质性或肝纤维化消退过程中促进HSC失活的相互作用中的免疫调节功能。了解HSC作为肝脏免疫学中心调节因子的作用可能会为慢性肝病带来新的治疗策略。
