Fan JH, Luo N, Liu GF, Xu XF, Li SQ, Lv XP. Mechanism of annexin A1/N-formylpeptide receptor regulation of macrophage function to inhibit hepatic stellate cell activation through Wnt/β-catenin pathway. World J Gastroenterol 2023; 29(22): 3422-3439 [PMID: 37389234 DOI: 10.3748/wjg.v29.i22.3422]
Corresponding Author of This Article
Jun-Hua Fan, Doctor, MD, PhD, Associate Professor, Doctor, Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, China. fanjunhuaxiaoshe@hotmail.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. Jun 14, 2023; 29(22): 3422-3439 Published online Jun 14, 2023. doi: 10.3748/wjg.v29.i22.3422
Mechanism of annexin A1/N-formylpeptide receptor regulation of macrophage function to inhibit hepatic stellate cell activation through Wnt/β-catenin pathway
Jun-Hua Fan, Na Luo, Geng-Feng Liu, Xiao-Fang Xu, Shi-Quan Li, Xiao-Ping Lv, Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
Author contributions: Fan JH, Luo N and Liu GF performed most of the experiments; Luo N, Xu XF and Li SQ analyzed the data; Fan JH and Lv XP designed the study and wrote the paper.
Supported bya Grant-in-Aid for Scientific Research from National Natural Science Foundation of China, No. 81860120 and 81860104; Guangxi Natural Science Foundation, No. 2017GXNSFBA198134, 2017GXNSFAA198299 and 2015GXNSFCA139024.
Institutional animal care and use committee statement: All experiments were conducted in accordance with the institutional guidelines of Guangxi Medical University for the care and use of laboratory animals.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jun-Hua Fan, Doctor, MD, PhD, Associate Professor, Doctor, Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning 530021, Guangxi Zhuang Autonomous Region, China. fanjunhuaxiaoshe@hotmail.com
Received: February 15, 2023 Peer-review started: February 15, 2023 First decision: March 28, 2023 Revised: April 10, 2023 Accepted: May 11, 2023 Article in press: May 11, 2023 Published online: June 14, 2023 Processing time: 111 Days and 17 Hours
Abstract
BACKGROUND
Hepatic fibrosis is a common pathological process of chronic liver diseases with various causes, which can progress to cirrhosis.
AIM
To evaluate the effect and mechanism of action annexin (Anx)A1 in liver fibrosis and how this could be targeted therapeutically.
METHODS
CCl4 (20%) and active N-terminal peptide of AnxA1 (Ac2-26) and N-formylpeptide receptor antagonist N-Boc-Phe-Leu-Phe-Leu-Phe (Boc2) were injected intraperitoneally to induce liver fibrosis in eight wild-type mice/Anxa1 knockout mice, and to detect expression of inflammatory factors, collagen deposition, and the role of the Wnt/β-catenin pathway in hepatic fibrosis.
RESULTS
Compared with the control group, AnxA1, transforming growth factor (TGF)-β1, interleukin (IL)-1β and IL-6 expression in the liver of mice with hepatic fibrosis induced by CCl4 was significantly increased, which promoted collagen deposition and expression of α-smooth muscle actin (α-SMA), collagen type I and connective tissue growth factor (CTGF), and increased progressively with time. CCl4 induced an increase in TGF-β1, IL-1β and IL-6 in liver tissue of AnxA1 knockout mice, and the degree of liver inflammation and fibrosis and expression of α-SMA, collagen I and CTGF were significantly increased compared with in wild-type mice. After treatment with Ac2-26, expression of liver inflammatory factors, degree of collagen deposition and expression of a-SMA, collagen I and CTGF were decreased compared with before treatment. Boc2 inhibited the anti-inflammatory and antifibrotic effects of Ac2-26. AnxA1 downregulated expression of the Wnt/β-catenin pathway in CCl4-induced hepatic fibrosis. In vitro, lipopolysaccharide (LPS) induced hepatocyte and hepatic stellate cell (HSC) expression of AnxA1. Ac2-26 inhibited LPS-induced RAW264.7 cell activation and HSC proliferation, decreased expression of α-SMA, collagen I and CTGF in HSCs, and inhibited expression of the Wnt/β-catenin pathway after HSC activation. These therapeutic effects were inhibited by Boc2.
CONCLUSION
AnxA1 inhibited liver fibrosis in mice, and its mechanism may be related to inhibition of HSC Wnt/β-catenin pathway activation by targeting formylpeptide receptors to regulate macrophage function.
Core Tip: Hepatic stellate cells (HSCs) are the main receiver of inflammatory signals and the main promoter of fibrosis. Kupffer cells are activated by damage-associated molecular patterns or lipopolysaccharide, and other pathogen-associated molecular patterns, producing and releasing cytokines to activate HSCs, causing secretion and deposition of extracellular matrix and liver fibrosis. Annexin (Anx)A1 is a glucocorticoid regulatory protein that enhances efferocytosis in macrophages, inhibits activation of phospholipase A2, downregulates expression of inflammatory arachidonic acid, and negatively regulates inflammatory cells and factors. Whether AnxA1 is involved in the formation of liver fibrosis and its mechanism of action were the focus of this study.
