Stressed hepatocyte sustains alcohol-associated hepatitis progression by producing leukocyte cell-derived chemotaxin 2

Honghai Xu; Zihao Wu; Jiangfeng Qin; Xutong Li; Feng Xu; Wei Wang; Hui Zhang; HeHe Yin; Shiwei Zhu; Wenzhe Zhang; Yuanru Yang; Yuanyuan Wei; Long Gao; Jiatao Liu; Yufeng Gao; Ming-Hua Zheng; Haoxiong Zhou; Tingting Qi; Jinjun Chen; Yanhang Gao; Li Zuo; Jiong Chen; Suthat Liangpunsakul; Jiabin Li; Hua Wang

doi:10.1136/gutjnl-2024-334318

Stressed hepatocyte sustains alcohol-associated hepatitis progression by producing leukocyte cell-derived chemotaxin 2

Gut. 2025 Mar 26:gutjnl-2024-334318. doi: 10.1136/gutjnl-2024-334318. Online ahead of print.

Authors

Honghai Xu^{1

2}, Zihao Wu^{3

4}, Jiangfeng Qin⁵, Xutong Li^{6

7}, Feng Xu⁸, Wei Wang¹, Hui Zhang^{1

9}, HeHe Yin^{1

9}, Shiwei Zhu¹, Wenzhe Zhang^{9

10}, Yuanru Yang¹¹, Yuanyuan Wei^{6

7}, Long Gao^{6

7}, Jiatao Liu¹², Yufeng Gao^{6

7}, Ming-Hua Zheng^{13

14}, Haoxiong Zhou¹⁵, Tingting Qi^{16

17}, Jinjun Chen^{17

18}, Yanhang Gao¹⁹, Li Zuo^{9

10}, Jiong Chen²⁰, Suthat Liangpunsakul²¹, Jiabin Li^{22

7}, Hua Wang^{23

24}

Affiliations

¹ Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
² Department of Pathology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
³ Department of Geriatrics, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, China.
⁴ Anhui Key Laboratory of Geriatric Immunology and Nutrition Therapy, Hefei, Anhui, China.
⁵ Department of Infectious Diseases, the People's Hospital of Xuancheng City, Xuancheng, Anhui, China.
⁶ Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
⁷ Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
⁸ Department of Intensive Care Unit & Central Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China.
⁹ Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China.
¹⁰ Laboratory of Molecular Biology, and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, China.
¹¹ Department of Blood Transfusion, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, Beijing, China.
¹² Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
¹³ MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
¹⁴ Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang, China.
¹⁵ Department of Gastroenterology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
¹⁶ Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
¹⁷ State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Hepatology, Guangdong Provincial Research Center for Liver Fibrosis Engineering and Technology, Guangzhou, Guangdong, China.
¹⁸ Hepatology Unit, Department of Infectious Diseases, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
¹⁹ Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China.
²⁰ State Key Laboratory for Quality and Safety of Agro-Products, School of Marine Sciences, Ningbo University, Ningbo, Zhejiang, China.
²¹ Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
²² Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China wanghua@ahmu.edu.cn lijiabin@ahmu.edu.cn.
²³ Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China wanghua@ahmu.edu.cn lijiabin@ahmu.edu.cn.
²⁴ Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China.

PMID: 40139745
DOI: 10.1136/gutjnl-2024-334318

Abstract

Background: Neutrophil infiltration and hepatocyte damage are indispensable hallmarks in alcohol-associated hepatitis (AH), yet the underlying crosstalk between neutrophils and hepatocytes and its role in AH pathogenesis remain unclear.

Objective: We investigate the regulatory role of leucocyte cell-derived chemotaxin 2 (LECT2) in hepatocyte-neutrophil interaction and its impact on AH progression.

Design: We used bulk and single-cell RNA sequencing to identify hepatocyte-secreted factors targeting neutrophils. We analysed serum and liver samples from AH patients and employed genetically modified mice alongside in vitro studies.

Results: RNA-sequencing analysis identified several neutrophil chemokines that are elevated in hepatocytes from AH patients, including LECT2 whose role in AH remains largely unknown. AH patients exhibited increased levels of LECT2 in hepatocytes, positively correlating with the severity of AH. Ethanol-fed mice also exhibited elevated liver LECT2, which was abolished by inhibiting endoplasmic reticulum stress. Functional studies revealed that ethanol-induced liver injury was ameliorated in Lect2-deficient mice but was exacerbated in mice with hepatic overexpression of Lect2. Furthermore, LECT2 exacerbated ethanol-induced liver injury by promoting reactive oxygen species (ROS) through its interaction with prohibitin 2 (PHB2), a neutrophil membrane protein. By directly binding to PHB2, LECT2 disrupts the stable structure of PHB1/PHB2 heterodimerisation, consequently leading to PHB2 degradation, ROS accumulation, neutrophil activation and neutrophil extracellular trap formation. Moreover, therapeutic intervention of LECT2 via Lect2 shRNA ameliorated ethanol-induced liver injury.

Conclusion: Our studies identified a novel vicious cycle between neutrophils and hepatocytes through the LECT2-PHB2 interaction, presenting a promising therapeutic intervention by targeting LECT2 to mitigate AH in patients.

Keywords: ALCOHOLIC LIVER DISEASE; HEPATOCYTE; INFLAMMATORY CELLS.