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Published on: June 29, 2012
PAD4+ neutrophils promote hepatic stellate cell activation and accelerate MASH fibrosis progression
Jiajia Shen1, Shanshan Huang2,3, Yaohui Wang4
1Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
Abstract:
Neutrophils play a pivotal role in the progression of metabolic dysfunction-associated steatohepatitis (MASH) by mediating inflammatory responses. However, the heterogeneity of neutrophil subsets in MASH and their specific contributions to disease progression remain unclear. In this study, analysis of liver biopsies from 265 patients revealed a strong association between elevated neutrophil counts and MASH severity, particularly fibrosis. Five distinct neutrophil subsets were identified in human liver tissue, with PAD4+ neutrophils serving as key drivers in MASH progression. Mechanistically, PAD4+ neutrophils generate neutrophil extracellular traps (NETs) and activate hepatic stellate cells via the TAOK1-dependent MAPK signaling pathway. Inhibition of PAD4+ neutrophils in vivo attenuated the progression of liver fibrosis without exacerbating liver injury. Collectively, these findings elucidate the pivotal involvement of PAD4+ neutrophils in MASH progression and identify them as promising therapeutic targets for mitigating fibrosis and inflammation.
Insights
Neutrophils drive metabolic dysfunction-associated steatohepatitis (MASH) progression, especially fibrosis. Targeting PAD4+ neutrophils, which form neutrophil extracellular traps (NETs), may offer a new therapy for MASH.
Area of Science:
- Hepatology
- Immunology
- Pathology
Background:
- Neutrophils are implicated in metabolic dysfunction-associated steatohepatitis (MASH) pathogenesis.
- The specific roles of neutrophil subsets in MASH progression are not well understood.
Purpose of the Study:
- To investigate the heterogeneity and function of neutrophil subsets in MASH.
- To identify key neutrophil populations driving MASH and fibrosis.
Main Methods:
- Analysis of liver biopsies from 265 MASH patients.
- Identification and characterization of distinct neutrophil subsets.
- In vivo studies to assess the therapeutic potential of targeting PAD4+ neutrophils.
Main Results:
- Elevated neutrophil counts correlate with MASH severity and fibrosis.
- PAD4+ neutrophils were identified as key drivers of MASH progression.
- PAD4+ neutrophils generate neutrophil extracellular traps (NETs) and activate hepatic stellate cells.
- Inhibition of PAD4+ neutrophils reduced liver fibrosis without increasing liver injury.
Conclusions:
- PAD4+ neutrophils play a critical role in MASH pathogenesis and fibrosis.
- Targeting PAD4+ neutrophils represents a promising therapeutic strategy for MASH.
- Further research into neutrophil subsets could lead to novel MASH treatments.
