2. Academic Validation
  3. Polyunsaturated fatty acids drive neutrophil extracellular trap formation in nonalcoholic steatohepatitis

Polyunsaturated fatty acids drive neutrophil extracellular trap formation in nonalcoholic steatohepatitis

  • Eur J Pharmacol. 2023 Feb 24;945:175618. doi: 10.1016/j.ejphar.2023.175618.
Jiawei Wu 1,  Chuan Zhang 1,  Tianyu He 1,  Shule Zhang 1,  Yun Wang 1,  Ziqing Xie 1,  Wanfeng Xu 1,  Chujie Ding 1,  Yubing Shuai 1,  Haiping Hao 2,  Lijuan Cao 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetic, China Pharmaceutical University, Nanjing, China.
  • 2 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetic, China Pharmaceutical University, Nanjing, China. Electronic address: haipinghao@cpu.edu.cn.
  • 3 State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetic, China Pharmaceutical University, Nanjing, China. Electronic address: caolijuan0702@cpu.edu.cn.
PMID: 36841284 DOI: 10.1016/j.ejphar.2023.175618
Abstract

Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome. Non-resolving inflammation, triggered by sustained accumulation of lipids, is an important driving force of NASH. Thus, unveiling metabolic immune regulation could help better understand the pathology and intervention of NASH. In this study, we found the recruitment of neutrophils is an early inflammatory event in NASH mice, following the formation of neutrophil extracellular traps (NETs). NET is an initiating factor which exacerbates inflammatory responses in macrophages. Inhibition of NETs using DNase I significantly alleviated inflammation in NASH mice. We further carried out a metabolomic study to identify possible metabolic triggers of NETs, and linoleic acid (LA) metabolic pathway was the most altered pathway. We re-analyzed published clinical data and validated that LA metabolism was highly correlated with NASH. Consistently, both LA and γ-linolenic acid (GLA) were active in triggering NETs formation by oxidative burst. Furthermore, we identified silybin, a hepatoprotective agent, as a potent NETosis inhibitor, which effectively blocked NETs formation both in vitro and in vivo. Together, this study not only provide new insights into metabolism-immune causal link in NASH progression, but also demonstrate silybin as an important inhibitor of NETs and its therapeutical potential in treating NETosis-related diseases.

Keywords

Inflammation; Linoleic acid; Neutrophil extracellular traps; Nonalcoholic steatohepatitis; Silybin; γ-linolenic acid.

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