NLRP3 inflammasome activation promotes liver inflammation and fibrosis in experimental biliary atresia

Junfeng Wang; Min Du; Lingdu Meng; Shiwei He; Ye Zhu; Yifan Yang; Xue Ren; Yanlei Huang; Song Sun; Rui Dong; Shan Zheng; Gong Chen

doi:10.1016/j.dld.2023.08.039

NLRP3 inflammasome activation promotes liver inflammation and fibrosis in experimental biliary atresia

Dig Liver Dis. 2024 Mar;56(3):458-467. doi: 10.1016/j.dld.2023.08.039. Epub 2023 Aug 25.

Authors

Junfeng Wang¹, Min Du², Lingdu Meng¹, Shiwei He¹, Ye Zhu¹, Yifan Yang¹, Xue Ren¹, Yanlei Huang¹, Song Sun¹, Rui Dong¹, Shan Zheng³, Gong Chen⁴

Affiliations

¹ Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai 201102, PR China.
² Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai 201102, PR China; Department of Pediatric Gastroenterology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610091, PR China.
³ Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai 201102, PR China. Electronic address: szheng@shmu.edu.cn.
⁴ Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai 201102, PR China. Electronic address: chengongzlp@fudan.edu.cn.

PMID: 37635054
DOI: 10.1016/j.dld.2023.08.039

Abstract

Background: Biliary atresia (BA) is characterized by a progressive fibroinflammatory cholangiopathy in early infants with unknown etiology. Although innate immune disorder is involved in its mechanism, role of NLRP3 inflammasome in BA remains largely undefined.

Aim: To explore the role of NLRP3 inflammasome in BA.

Methods: The expressions of NLRP3 inflammasome-related genes were determined in BA patients. Role of NLRP3 inflammasome was evaluated using MCC950 in experimental BA. Furthermore, gadolinium chloride, a macrophage scavenger, was applied to validate the inflammasome's cellular localization. Finally, the effects of NLRP3 inflammasome activation on liver fibrosis were explored in vivo and vitro in experimental BA.

Results: The components of NLRP3 inflammasome were up-regulated in BA patients. Inflammasome-related genes showed positively correlated with liver inflammation and fibrosis in BA patients. In experimental BA, inflammasome-related genes were up-regulated, and their expressions were inhibited by MCC950, which promoted mice growth, protected liver function, alleviated obstructive jaundice, inhibited liver inflammation, and reduced serum IL-1β level. NLRP3 inflammasome was expressed in macrophages, and macrophage elimination exerted the same protective roles as MCC950 did in BA. Additionally, NLRP3 inflammasome activation promoted liver fibrosis in experimental BA.

Conclusions: NLRP3 inflammasome activation in macrophages promoted liver inflammation and fibrosis in experimental BA.

Keywords: Biliary atresia; Liver fibrosis; Liver inflammation; NLRP3 inflammasome.

MeSH terms

Animals
Biliary Atresia*
Fibrosis
Humans
Inflammasomes* / metabolism
Inflammation
Liver Cirrhosis
Mice
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Sulfonamides / pharmacology

Substances

Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
Sulfonamides