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Oral FPR2/ALX modulators tune myeloid cell activity to ameliorate mucosal inflammation in inflammatory bowel disease

Acta Pharmacologica Sinica volume 46, pages 1958–1973 (2025)Cite this article

Abstract

Current treatments of inflammatory bowel disease (IBD) largely depend on anti-inflammatory and immunosuppressive strategies with unacceptable efficacy and adverse events. Resolution or repair agents to treat IBD are not available but potential targets like formyl peptide receptor 2 (FPR2/ALX) may fill the gap. In this study we evaluated the therapeutic effects of two small molecule FPR2/ALX modulators (agonist Quin-C1 and antagonist Quin-C7) against IBD. We first analyzed the cryo-electron microscopy structure of the Quin-C1–FPR2 in complex with heterotrimeric Gi to reveal the structural basis for ligand recognition and FPR2 activation. We then established dextran sulfate sodium (DSS)-induced colitis model in both normal and myeloid depletion mice. We showed that oral administration of Quin-C1 for 7 days ameliorated DSS-induced colitis evidenced by alleviated disease activity indexes, reduced colonic histopathological scores, and corrected cytokine disorders. Meanwhile, we found that oral administration of FPR2/ALX antagonist Quin-C7 exerted therapeutic actions similar to those of Quin-C1. In terms of symptomatic improvements, the ED50 values of Quin-C1 and Quin-C7 were 1.3660 mg/kg and 2.2110 mg/kg, respectively. The underlying mechanisms involved ERK- or ERK/JNK-mediated myeloid cell regulation that limited the development of colitis and inflammation. This is the first demonstration of anti-colitis property caused by synthetic small molecule FPR2/ALX modulators, implying that FPR2/ALX modulation rather than agonism alone ameliorates IBD.

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Fig. 1: Molecular recognition of Quin-C1 by FPR2.
Fig. 2: Anti-colitis effects of QC1.
Fig. 3: Dose-response characteristics of QC1 and QC7.
Fig. 4: Relief of colonic inflammation by QC1.
Fig. 5: Inflammatory mediators and myeloid cells associated with QC1/QC7 treatment.
Fig. 6: Effects of QC1 and QC7 on myeloid cells from splenic and colonic tissues in DSS mice.
Fig. 7: Effects of myeloid depletion on QC1/QC7 treatment.
Fig. 8: Signaling pathways related to QC1/QC7 treatment.
Fig. 9: Proposed mechanisms by which oral FPR2/ALX modulators tune myeloid cell activity to ameliorate mucosal inflammation in inflammatory bowel disease.

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Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. The atomic coordinate has been deposited in the Protein Data Bank (PDB) under accession code: 8ZBW (QC1–FPR2–Gi), and the electron microscopy map has been deposited in the Electron Microscopy Data Bank (EMDB) under accession code: EMD-39915 (QC1–FPR2–Gi). Additional data related to this paper may be requested from the authors.

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Acknowledgements

We are indebted to De-hua Yang (The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences) for valuable discussions, to Xiao-yan Wu (The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences) for technical assistance, and to Ming-qing Yuan (Department of Clinical Pharmacy, Kunshan Maternity and Children’s Health Care Hospital, Children’s Hospital of Fudan University Kunshan Branch) for critical review of the manuscript. The cryo-EM data were collected at the Cryo-Electron Microscopy Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences. This work was partially supported by the National Natural Science Foundation of China 82273961 (MWW), 82073904 (MWW) and 81872915 (MWW); Shanghai Hospital Development Center Foundation SHDC22024204 (ZPL), Shanghai Medicine and Health Development Foundation 20221128 (ZPL) and Shanghai Municipal Human Resources and Social Security Bureau EK00000861 (ZPL); STI2030-Major Project 2021ZD0203400 (QTZ) and Hainan Provincial Major Science and Technology Project ZDKJ2021028 (QTZ).

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  1. These authors contributed equally: Wen-sheng Yang, Qing Liu

Authors and Affiliations

  1. Department of Clinical Pharmacy, Children’s Hospital of Fudan University, National Children’s Medical Center, Shanghai, 201102, China

    Wen-sheng Yang, Lin-yu Li, Xi-lin Ge, Wei Wu, Guang-fei Wang & Zhi-ping Li

  2. The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Qing Liu

  3. Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China

    Yang Li, Jie Li, Qing-tong Zhou & Ming-Wei Wang

  4. School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China

    Guan-yi Li

  5. Research Center for Deepsea Bioresources, Sanya, 572025, China

    Shi Lin, Yuan Li, Xiao-zhen Wang, Qing-tong Zhou & Ming-Wei Wang

  6. Department of Laboratory Animal Science, Fudan University, Shanghai, 200032, China

    Jun Yan

  7. Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Qing-tong Zhou & Ming-Wei Wang

  8. Department of Neurology, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Qiang Liu

  9. Department of Clinical Pharmacy, Kunshan Maternity and Children’s Health Care Hospital, Children’s Hospital of Fudan University Kunshan Branch, Kunshan, 215300, China

    Zhi-ping Li

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Contributions

WSY, ZPL and MWW designed research; WSY, MWW, Qiang Liu, and JY contributed to methodology; WSY, Qing Liu, LYL, Yuan Li, Yang Li, SL, GYL, XLG, XZW, JL, GFW and WW performed experiments; WSY, MWW, and QTZ analyzed data; MWW and ZPL supervised the project; WSY, QTZ, ZPL and MWW wrote the manuscript. All authors have reviewed and approved the manuscript.

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Correspondence to Ming-Wei Wang or Zhi-ping Li.

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Yang, Ws., Liu, Q., Li, Y. et al. Oral FPR2/ALX modulators tune myeloid cell activity to ameliorate mucosal inflammation in inflammatory bowel disease. Acta Pharmacol Sin 46, 1958–1973 (2025). https://doi.org/10.1038/s41401-025-01525-7

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