Yang Ming, Vanderwert Ethan, Kimchi Eric T, Staveley-O'Carroll Kevin F, Li Guangfu
Department of Surgery, University of Missouri, Columbia, MO 65212, USA.
NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA.
Biomedicines. 2023 May 8;11(5):1391. doi: 10.3390/biomedicines11051391.
Liver fibrosis accompanies the development of various chronic liver diseases and promotes their progression. It is characterized by the abnormal accumulation of extracellular matrix proteins (ECM) and impaired ECM degradation. Activated hepatic stellate cells (HSCs) are the major cellular source of ECM-producing myofibroblasts. If liver fibrosis is uncontrolled, it may lead to cirrhosis and even liver cancer, primarily hepatocellular carcinoma (HCC). Natural killer (NK) cells are a key component of innate immunity and have miscellaneous roles in liver health and disease. Accumulating evidence shows that NK cells play dual roles in the development and progression of liver fibrosis, including profibrotic and anti-fibrotic functions. Regulating NK cells can suppress the activation of HSCs and improve their cytotoxicity against activated HSCs or myofibroblasts to reverse liver fibrosis. Cells such as regulatory T cells (Tregs) and molecules such as prostaglandin E receptor 3 (EP) can regulate the cytotoxic function of NK cells. In addition, treatments such as alcohol dehydrogenase 3 (ADH3) inhibitors, microRNAs, natural killer group 2, member D (NKG2D) activators, and natural products can enhance NK cell function to inhibit liver fibrosis. In this review, we summarized the cellular and molecular factors that affect the interaction of NK cells with HSCs, as well as the treatments that regulate NK cell function against liver fibrosis. Despite a lot of information about NK cells and their interaction with HSCs, our current knowledge is still insufficient to explain the complex crosstalk between these cells and hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, B cells, and T cells, as well as thrombocytes, regarding the development and progression of liver fibrosis.
肝纤维化伴随各种慢性肝病的发展，并促进其进展。其特征是细胞外基质蛋白（ECM）异常积累以及ECM降解受损。活化的肝星状细胞（HSC）是产生ECM的肌成纤维细胞的主要细胞来源。如果肝纤维化得不到控制，可能会导致肝硬化甚至肝癌，主要是肝细胞癌（HCC）。自然杀伤（NK）细胞是固有免疫的关键组成部分，在肝脏健康和疾病中发挥多种作用。越来越多的证据表明，NK细胞在肝纤维化的发生和发展中发挥双重作用，包括促纤维化和抗纤维化功能。调节NK细胞可以抑制HSC的活化，并提高其对活化的HSC或肌成纤维细胞的细胞毒性，从而逆转肝纤维化。调节性T细胞（Treg）等细胞和前列腺素E受体3（EP）等分子可以调节NK细胞的细胞毒性功能。此外，酒精脱氢酶3（ADH3）抑制剂、微小RNA、自然杀伤细胞2族D成员（NKG2D）激活剂和天然产物等治疗方法可以增强NK细胞功能以抑制肝纤维化。在本综述中，我们总结了影响NK细胞与HSC相互作用的细胞和分子因素，以及调节NK细胞抗肝纤维化功能的治疗方法。尽管有很多关于NK细胞及其与HSC相互作用的信息，但我们目前的知识仍然不足以解释这些细胞与肝细胞、肝窦内皮细胞、库普弗细胞、B细胞和T细胞以及血小板之间关于肝纤维化发生和发展的复杂串扰。
