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The role of neutrophils in innate immunity-driven nonalcoholic steatohepatitis: lessons learned and future promise

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Abstract

The enrichment of innate immune cells and the enhanced inflammation represent the hallmark of non-alcoholic steatohepatitis (NASH), the advanced subtype with a significantly increased risk of progression to end-stage liver diseases within the spectrum of non-alcoholic fatty liver disease. Neutrophils are traditionally recognized as key components in the innate immune system to defend against pathogens. Recently, a growing body of evidence supports neutrophils as emerging key player in mediating the transition from steatosis to NASH, which is largely inspired by the histological findings in human liver biopsy indicating the enhanced infiltration of neutrophils as one of the key histological features of NASH. In this review, we discuss data regarding histological perspectives of hepatic infiltration of neutrophils in NASH. We also highlight the pathophysiological role of neutrophils in promoting metabolic inflammation in the liver through the release of a vast array of granule proteins, the interaction with other pro-inflammatory immune cells, and the formation of neutrophil extracellular traps. Neutrophil granule proteins possess pleiotropic effects on regulating neutrophil biology and functions. A variety of granule proteins (including lipocalin-2, myeloperoxidase, proteinase 3, neutrophil elastase, etc.) produced by neutrophils enhance liver metabolic inflammation, thereby promoting NASH progression by mediating neutrophil-macrophage interaction. Therapeutically, pharmacological inhibitors targeting neutrophil granule proteins hold promise to combat NASH. In addition, this article also summarizes potentials of neutrophils and its derived various granule proteins for the accurate, even non-invasive diagnosis of NASH.

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Abbreviations

ALD:

Alcoholic liver disease

CCL:

CC-chemokine ligand

CXCL:

CXC-chemokine ligand

CXCR:

CXC chemokine/motif receptor

DCs:

Dendritic cells

ECM:

Extracellular matrix

G-CSF:

Granulocyte colony stimulating factor

HSCs:

Hepatic stellate cells

IL-1α:

Interleukin-1α

LCN2:

Lipocalin-2

LPS:

Lipopolysaccharide

Ly6G:

Lymphocyte antigen 6 complex locus G6D

MCD:

Methionine- and choline-deficient

MPO:

Myeloperoxidase

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Non-alcoholic steatohepatitis

NE:

Neutrophil elastase

NET:

Neutrophil extracellular trap

NF-κB:

Nuclear factor-κB

NGAL:

Neutrophil gelatinase-related lipocalin

NK cells:

Natural killer cells

NKT cells:

Natural killer T cells

NLR:

Neutrophil-to-lymphocyte ratio

PR3:

Proteinase 3

ROS:

Reactive oxygen species

TLR:

Toll like receptor

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Acknowledgements

Research in the authors’ laboratory is financially supported by NSFC Grant (81570701, 81770849, 81830113), Key Research Program in Department of Education of Guangdong Province (2016KZDXM041), Key Laboratory of Model Animal Phenotyping and Basic Research in Metabolic Diseases (2018KSYS003), Major basic and applied basic research projects in Guangdong Province (2019B030302005), Research Fund in TCM Bureau of Guangdong Province (20181156).

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  1. Key Laboratory of Glucolipid Metabolic Diseases of the Ministry of Education, Guangzhou Higher Education Mega, Guangdong Pharmaceutical University, Lab 406, 4th Floor, Science and Technology Building, 280 Waihuan East Road, Guangzhou, China

    Lihong Wu, Xiang Gao, Qianyu Guo, Jufei Li, Jianyu Yao, Kaixuan Yan, Xue Jiang, Dewei Ye & Jiao Guo

  2. Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Guangzhou Higher Education Mega, Guangdong Pharmaceutical University, Room 403, 4th Floor, Science and Technology Building, 280 Waihuan East Road, Guangzhou, China

    Lihong Wu, Xiang Gao, Qianyu Guo, Jufei Li, Jianyu Yao, Kaixuan Yan, Xue Jiang, Dewei Ye & Jiao Guo

  3. The First Affiliated Hospital/School of Clinical Medicine, Guangdong Pharmaceutical University, Guangzhou, China

    Ying Xu

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  1. Lihong Wu
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  2. Xiang Gao
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  9. Dewei Ye
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  10. Jiao Guo
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Correspondence to Dewei Ye or Jiao Guo.

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Lihong Wu, Xiang Gao, Qianyu Guo, Jufei Li, Jianyu Yao, Kaixuan Yan, Ying Xu, Xue Jiang, Dewei Ye, Jiao Guo have no conflict to declare.

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Wu, L., Gao, X., Guo, Q. et al. The role of neutrophils in innate immunity-driven nonalcoholic steatohepatitis: lessons learned and future promise. Hepatol Int 14, 652–666 (2020). https://doi.org/10.1007/s12072-020-10081-7

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