@article{a3993254de3b4c6a82429b9bd5b915b3,
title = "Enhancement of efferocytosis through biased FPR2 signaling attenuates intestinal inflammation",
abstract = "Efficient clearance of dying cells (efferocytosis) is an evolutionarily conserved process for tissue homeostasis. Genetic enhancement of efferocytosis exhibits therapeutic potential for inflammation resolution and tissue repair. However, pharmacological approaches to enhance efferocytosis remain sparse due to a lack of targets for modulation. Here, we report the identification of columbamine (COL) which enhances macrophage-mediated efferocytosis and attenuates intestinal inflammation in a murine colitis model. COL enhances efferocytosis by promoting LC3-associated phagocytosis (LAP), a non-canonical form of autophagy. Transcriptome analysis and pharmacological characterization revealed that COL is a biased agonist that occupies a part of the ligand binding pocket of formyl peptide receptor 2 (FPR2), a G-protein coupled receptor involved in inflammation regulation. Genetic ablation of the Fpr2 gene or treatment with an FPR2 antagonist abolishes COL-induced efferocytosis, anti-colitis activity and LAP. Taken together, our study identifies FPR2 as a potential target for modulating LC3-associated efferocytosis to alleviate intestinal inflammation and highlights the therapeutic value of COL, a natural and biased agonist of FPR2, in the treatment of inflammatory bowel disease.",
keywords = "columbamine, FPR2, inflammatory bowel disease, LC3-associated efferocytosis",
author = "Wu, {Ming Yue} and Ge, {Yun Jun} and Wang, {Er Jin} and Liao, {Qi Wen} and Ren, {Zheng Yu} and Yang Yu and Guoyuan Zhu and Liu, {Chun Ping} and Zhang, {Meng Ni} and Huanxing Su and Shen, {Han Ming} and Ye Chen and Lei Wang and Wang, {Yi Tao} and Min Li and Zhaoxiang Bian and Jin Chai and Ye, {Richard D} and Lu, {Jia Hong}",
note = "Funding information: This work was supported by Shenzhen Fundamental Research Program (No. SGDX20210823103804030), The Science and Technology Development Fund, Macau SAR (File no. 0025/2022/A1, 0128/2019/A3), The University of Macau grants (No. MYRG2022‐00094‐ICMS), National Natural Science Foundation of China (No. 82271455; 32070950; 82104183), The Guangdong Basic and Applied Basic Research Foundation (No. 2022A1515012416), and The 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund (Guangdong‐Hong Kong‐Macau Joint Lab, No: 2020B1212030006) awarded to Jia‐Hong Lu. This work is also partially supported by The Science Technology and Innovation Commission of Shenzhen Municipality (File no. GXWD20201231105722002‐20200831175432002, JCYJ20200109150019113), and Joint Research Fund of the Second Affiliated Hospital‐School of Medicine, The Chinese University of Hong Kong, Shenzhen awarded to Richard D. Ye and National Natural Science Foundation of China (No. 82200585) awarded to Ming‐Yue Wu. We thank Dr. Mizushima (Tokyo Medical and Dental University, Japan) for providing the GFP‐LC3 mice. We thank Suro in Bioimaging Core in Faculty of Health Sciences (University of Macau) for technique supports on time‐lapse images. Publisher Copyright: {\textcopyright} 2023 The Authors. Published under the terms of the CC BY 4.0 license.",
year = "2023",
month = dec,
day = "7",
doi = "10.15252/emmm.202317815",
language = "English",
volume = "15",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "12",
}
