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 r...
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| Format: | Article |
| Language: | English |
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Springer Nature
2023-11-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202317815 |
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| author | Ming‐Yue Wu Yun‐Jun Ge Er‐Jin Wang Qi‐Wen Liao Zheng‐Yu Ren Yang Yu Guoyuan Zhu Chun‐Ping Liu Meng‐Ni Zhang Huanxing Su Han‐Ming Shen Ye Chen Lei Wang Yi‐Tao Wang Min Li Zhaoxiang Bian Jin Chai Richard D Ye Jia‐Hong Lu |
| author_facet | Ming‐Yue Wu Yun‐Jun Ge Er‐Jin Wang Qi‐Wen Liao Zheng‐Yu Ren Yang Yu Guoyuan Zhu Chun‐Ping Liu Meng‐Ni Zhang Huanxing Su Han‐Ming Shen Ye Chen Lei Wang Yi‐Tao Wang Min Li Zhaoxiang Bian Jin Chai Richard D Ye Jia‐Hong Lu |
| author_sort | Ming‐Yue Wu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2a73d763915d475b830783a8ca0d9a89 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-2a73d763915d475b830783a8ca0d9a892025-08-20T03:46:19ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-11-01151212210.15252/emmm.202317815Enhancement of efferocytosis through biased FPR2 signaling attenuates intestinal inflammationMing‐Yue Wu0Yun‐Jun Ge1Er‐Jin Wang2Qi‐Wen Liao3Zheng‐Yu Ren4Yang Yu5Guoyuan Zhu6Chun‐Ping Liu7Meng‐Ni Zhang8Huanxing Su9Han‐Ming Shen10Ye Chen11Lei Wang12Yi‐Tao Wang13Min Li14Zhaoxiang Bian15Jin Chai16Richard D Ye17Jia‐Hong Lu18State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauKobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong KongState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauKobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong KongState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauEngineering Research Center of Cell and Therapeutic Antibody Medicine, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong UniversityState Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and TechnologyState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauDepartment of Gastroenterology, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University)State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauFaculty of Health Sciences, University of MacauIntegrative Microecology Center, Department of Gastroenterology, Shenzhen Hospital, Southern Medical UniversityDepartment of Cardiovascular Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese MedicineState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauSchool of Chinese Medicine, Hong Kong Baptist UniversitySchool of Chinese Medicine, Hong Kong Baptist UniversityDepartment of Gastroenterology, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University)Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong KongState Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of MacauAbstract 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.https://doi.org/10.15252/emmm.202317815columbamineFPR2inflammatory bowel diseaseLC3‐associated efferocytosis |
| spellingShingle | Ming‐Yue Wu Yun‐Jun Ge Er‐Jin Wang Qi‐Wen Liao Zheng‐Yu Ren Yang Yu Guoyuan Zhu Chun‐Ping Liu Meng‐Ni Zhang Huanxing Su Han‐Ming Shen Ye Chen Lei Wang Yi‐Tao Wang Min Li Zhaoxiang Bian Jin Chai Richard D Ye Jia‐Hong Lu Enhancement of efferocytosis through biased FPR2 signaling attenuates intestinal inflammation EMBO Molecular Medicine columbamine FPR2 inflammatory bowel disease LC3‐associated efferocytosis |
| title | Enhancement of efferocytosis through biased FPR2 signaling attenuates intestinal inflammation |
| title_full | Enhancement of efferocytosis through biased FPR2 signaling attenuates intestinal inflammation |
| title_fullStr | Enhancement of efferocytosis through biased FPR2 signaling attenuates intestinal inflammation |
| title_full_unstemmed | Enhancement of efferocytosis through biased FPR2 signaling attenuates intestinal inflammation |
| title_short | Enhancement of efferocytosis through biased FPR2 signaling attenuates intestinal inflammation |
| title_sort | enhancement of efferocytosis through biased fpr2 signaling attenuates intestinal inflammation |
| topic | columbamine FPR2 inflammatory bowel disease LC3‐associated efferocytosis |
| url | https://doi.org/10.15252/emmm.202317815 |
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