The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, United States.
Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Front Immunol. 2021 Apr 29;12:682736. doi: 10.3389/fimmu.2021.682736. eCollection 2021.
Liver diseases represent a major global health burden accounting for approximately 2 million deaths per year worldwide. The liver functions as a primary immune organ that is largely enriched with various innate immune cells, including macrophages, dendritic cells, neutrophils, NK cells, and NKT cells. Activation of these cells orchestrates the innate immune response and initiates liver inflammation in response to the danger signal from pathogens or injured cells and tissues. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial signaling cascade of the innate immune system activated by cytosol DNA. Recognizing DNA as an immune-stimulatory molecule is an evolutionarily preserved mechanism in initiating rapid innate immune responses against microbial pathogens. The cGAS is a cytosolic DNA sensor eliciting robust immunity the production of cyclic GMP-AMPs that bind and activate STING. Although the cGAS-STING pathway has been previously considered to have essential roles in innate immunity and host defense, recent advances have extended the role of the cGAS-STING pathway to liver diseases. Emerging evidence indicates that overactivation of cGAS-STING may contribute to the development of liver disorders, implying that the cGAS-STING pathway is a promising therapeutic target. Here, we review and discuss the role of the cGAS-STING DNA-sensing signaling pathway in a variety of liver diseases, including viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), primary hepatocellular cancer (HCC), and hepatic ischemia-reperfusion injury (IRI), with highlights on currently available therapeutic options.
肝脏疾病是全球主要的健康负担之一，每年导致全球约 200 万人死亡。肝脏作为主要的免疫器官，富含各种固有免疫细胞，包括巨噬细胞、树突状细胞、中性粒细胞、自然杀伤细胞和 NKT 细胞。这些细胞的激活协调固有免疫反应，并在病原体或受损细胞和组织发出危险信号时引发肝脏炎症。环鸟苷酸-腺苷酸合酶（cGAS）-干扰素基因刺激物（STING）途径是固有免疫系统的一个关键信号级联反应，由细胞质 DNA 激活。将 DNA 识别为免疫刺激性分子是启动针对微生物病原体的快速固有免疫反应的一种进化上保守的机制。cGAS 是一种细胞质 DNA 传感器，可引发强烈的免疫反应，产生与 STING 结合并激活 STING 的环鸟苷酸-AMP。尽管 cGAS-STING 途径以前被认为在固有免疫和宿主防御中具有重要作用，但最近的进展已经将 cGAS-STING 途径的作用扩展到肝脏疾病。新出现的证据表明，cGAS-STING 的过度激活可能导致肝脏疾病的发展，这意味着 cGAS-STING 途径是一个有前途的治疗靶点。在这里，我们综述并讨论了 cGAS-STING DNA 传感信号通路在各种肝脏疾病中的作用，包括病毒性肝炎、非酒精性脂肪性肝病（NAFLD）、酒精性肝病（ALD）、原发性肝癌（HCC）和肝缺血再灌注损伤（IRI），并重点介绍了目前可用的治疗选择。
