Charan Harsh Vardhan, Dwivedi Durgesh Kumar, Khan Sabbir, Jena Gopabandhu
Facility for Risk Assessment and Intervention Studies, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab 160062, India.
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Genes Dis. 2022 Jan 6;10(2):480-494. doi: 10.1016/j.gendis.2021.12.006. eCollection 2023 Mar.
The liver injury leads to an inflammatory response, which causes the activation of hepatic stellate cells (HSCs) that further secrete ECM proteins and play an important role in liver fibrosis. Moreover, the inflammatory response is a driving force for fibrogenesis, which is triggered by many types of injuries. Exaggerated inflammatory immune responses are mediated by cytoplasmic protein complexes known as inflammasomes, which are involved in many chronic liver diseases. Inflammasomes are pattern recognition receptors (PRRs) that can sense any microbial motifs known as pathogen-associated molecular patterns (PAMPs), and host- or environmental-derived stress signals known as damage-associated molecular patterns (DAMPs). The inflammasomes cause caspase-mediated proteolytic cleavage of pro-IL-1β and pro-IL-18 into active IL-1β and IL-18. In this review, we provide a comprehensive summary of the important roles of NLRP3 inflammasome in the pathogenesis of liver fibrosis with an emphasis on several direct and indirect pathways responsible for the NLRP3 inflammasome-mediated HSCs activation and fibrogenesis. In addition, we discuss the general pharmacological and genetics strategies for the inhibition of NLRP3 inflammasome activation and its downstream signaling with examples of emerging pharmacotherapeutics, targeting the NLRP3 inflammasome signaling as well as a possible way to develop effective and safer NLRP3 inflammasome inhibitors.
肝损伤会引发炎症反应，这会导致肝星状细胞（HSCs）活化，肝星状细胞会进一步分泌细胞外基质（ECM）蛋白，并在肝纤维化过程中发挥重要作用。此外，炎症反应是纤维化形成的驱动力，由多种类型的损伤引发。过度的炎症免疫反应由被称为炎性小体的细胞质蛋白复合物介导，炎性小体参与许多慢性肝病。炎性小体是模式识别受体（PRRs），能够感知任何被称为病原体相关分子模式（PAMPs）的微生物基序，以及被称为损伤相关分子模式（DAMPs）的宿主或环境来源的应激信号。炎性小体导致半胱天冬酶介导的前白细胞介素-1β（pro-IL-1β）和前白细胞介素-18（pro-IL-18）蛋白水解切割成活性白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）。在本综述中，我们全面总结了NLRP3炎性小体在肝纤维化发病机制中的重要作用，重点阐述了负责NLRP3炎性小体介导的肝星状细胞活化和纤维化形成的几种直接和间接途径。此外，我们讨论了抑制NLRP3炎性小体活化及其下游信号传导的一般药理学和遗传学策略，并举例说明了新兴的药物治疗方法，这些方法靶向NLRP3炎性小体信号传导，以及开发有效且更安全的NLRP3炎性小体抑制剂的可能途径。
