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

文献类型：期刊论文

作者Yang, Wen-sheng8; Liu, Qing9; Li, Yang2; Li, Guan-yi3; Lin, Shi4; Li, Jie2; Li, Lin-yu8; Li, Yuan4; Ge, Xi-lin8; Wang, Xiao-zhen4
刊名ACTA PHARMACOLOGICA SINICA
出版日期2025-03-11
页码16
关键词IBD FPR2/ALX Quin-C1 Quin-C7 neutrophils macrophages
ISSN号1671-4083
DOI10.1038/s41401-025-01525-7
通讯作者Wang, Ming-Wei(mwwang@simm.ac.cn) ; Li, Zhi-ping(zpli@fudan.edu.cn)
英文摘要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.
WOS关键词RESOLUTION ; MEDIATORS ; COLITIS ; MODELS ; AGONISTS ; LIGAND ; MICE ; IBD
资助项目Shanghai Institute of Materia Medica, Chinese Academy of Sciences ; National Natural Science Foundation of China[82273961] ; National Natural Science Foundation of China[82073904] ; National Natural Science Foundation of China[81872915] ; Shanghai Hospital Development Center Foundation[SHDC22024204] ; Shanghai Medicine and Health Development Foundation[20221128] ; Shanghai Municipal Human Resources and Social Security Bureau[EK00000861] ; Shanghai Municipal Human Resources and Social Security Bureau[2021ZD0203400] ; Hainan Provincial Major Science and Technology Project[ZDKJ2021028]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001441580600001
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/316520]  
专题中国科学院上海药物研究所
通讯作者Wang, Ming-Wei; Li, Zhi-ping
作者单位1.Shanghai Jiao Tong Univ, Res Ctr Med Struct Biol, Natl Res Ctr Translat Med Shanghai, State Key Lab Med Genom,Ruijin Hosp,Sch Med, Shanghai 200025, Peoples R China
2.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China
3.Shanghai Jiao Tong Univ, Sch Pharmaceut Sci, Shanghai 200240, Peoples R China
4.Res Ctr Deepsea Bioresources, Sanya 572025, Peoples R China
5.Fudan Univ, Dept Lab Anim Sci, Shanghai 200032, Peoples R China
6.Tianjin Med Univ, Gen Hosp, Dept Neurol, Tianjin 300052, Peoples R China
7.Fudan Univ, Kunshan Matern & Childrens Hlth Care Hosp, Dept Clin Pharm, Childrens Hosp,Kunshan Branch, Kunshan 215300, Peoples R China
8.Fudan Univ, Natl Childrens Med Ctr, Dept Clin Pharm, Childrens Hosp, Shanghai 201102, Peoples R China
9.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Wen-sheng,Liu, Qing,Li, Yang,et al. Oral FPR2/ALX modulators tune myeloid cell activity to ameliorate mucosal inflammation in inflammatory bowel disease[J]. ACTA PHARMACOLOGICA SINICA,2025:16.
APA Yang, Wen-sheng.,Liu, Qing.,Li, Yang.,Li, Guan-yi.,Lin, Shi.,...&Li, Zhi-ping.(2025).Oral FPR2/ALX modulators tune myeloid cell activity to ameliorate mucosal inflammation in inflammatory bowel disease.ACTA PHARMACOLOGICA SINICA,16.
MLA Yang, Wen-sheng,et al."Oral FPR2/ALX modulators tune myeloid cell activity to ameliorate mucosal inflammation in inflammatory bowel disease".ACTA PHARMACOLOGICA SINICA (2025):16.

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来源：上海药物研究所

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