TY - JOUR
T1 - Mechanisms of NLRP3 inflammasome-mediated hepatic stellate cell activation
T2 - Therapeutic potential for liver fibrosis
AU - Charan, Harsh Vardhan
AU - Dwivedi, Durgesh Kumar
AU - Khan, Sabbir
AU - Jena, Gopabandhu
N1 - Publisher Copyright:
© 2022 Chongqing Medical University
PY - 2023/3
Y1 - 2023/3
N2 - 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.
AB - 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.
KW - Hepatic stellate cells
KW - Liver fibrosis
KW - NLRP3 activation
KW - NLRP3 inflammasome
KW - NLRP3 inhibitors
UR - http://www.scopus.com/inward/record.url?scp=85123680650&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85123680650&partnerID=8YFLogxK
U2 - 10.1016/j.gendis.2021.12.006
DO - 10.1016/j.gendis.2021.12.006
M3 - Review article
C2 - 37223529
AN - SCOPUS:85123680650
SN - 2352-4820
VL - 10
SP - 480
EP - 494
JO - Genes and Diseases
JF - Genes and Diseases
IS - 2
ER -