Mechanisms of NLRP3 inflammasome- mediated hepatic stellate cell activation: Therapeutic potential for liver fibrosis

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 trig-gered 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 mi-crobial 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-113 and pro-IL-18 into active IL-113 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.(c) 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Automated summary

Liver injury induces an inflammatory response, leading to the activation of hepatic stellate cells (HSCs) that secrete ECM proteins and promote liver fibrosis. Inflammasomes, which are cytoplasmic protein complexes, mediate exaggerated inflammatory immune responses and contribute to chronic liver diseases. They recognize microbial motifs and damage-associated molecular patterns, leading to the production of active cytokines. This review provides a comprehensive summary of the role of NLRP3 inflammasome in liver fibrosis and discusses potential strategies for inhibiting its activation and downstream signaling.