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

IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Acta Pharmacologica Sinica Pub Date : 2025-07-01 Epub Date: 2025-03-11 DOI:10.1038/s41401-025-01525-7
Wen-Sheng Yang, Qing Liu, Yang Li, Guan-Yi Li, Shi Lin, Jie Li, Lin-Yu Li, Yuan Li, Xi-Lin Ge, Xiao-Zhen Wang, Wei Wu, Jun Yan, Guang-Fei Wang, Qing-Tong Zhou, Qiang Liu, Ming-Wei Wang, Zhi-Ping Li
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引用次数: 0

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.

口服FPR2/ALX调节剂调节骨髓细胞活性,改善炎症性肠病的粘膜炎症。
目前炎症性肠病(IBD)的治疗很大程度上依赖于抗炎和免疫抑制策略,其疗效和不良事件令人难以接受。目前尚没有治疗IBD的解决或修复药物,但甲酰基肽受体2 (FPR2/ALX)等潜在靶点可能填补这一空白。在这项研究中,我们评估了两种小分子FPR2/ALX调节剂(激动剂Quin-C1和拮抗剂Quin-C7)对IBD的治疗效果。我们首先分析了Quin-C1-FPR2与异三聚体Gi配合物的低温电镜结构,揭示了配体识别和FPR2激活的结构基础。然后,我们建立了正常小鼠和髓系衰竭小鼠的葡聚糖硫酸钠(DSS)诱导的结肠炎模型。我们发现,口服Quin-C1 7天可以改善dss诱导的结肠炎,这可以通过减轻疾病活动性指数、降低结肠组织病理学评分和纠正细胞因子紊乱来证明。同时,我们发现口服FPR2/ALX拮抗剂Quin-C7具有与Quin-C1相似的治疗作用。在症状改善方面,Quin-C1和Quin-C7的ED50值分别为1.3660 mg/kg和2.2110 mg/kg。潜在的机制涉及ERK-或ERK/ jnk介导的髓细胞调节,限制了结肠炎和炎症的发展。这是合成小分子FPR2/ALX调节剂引起的抗结肠炎特性的首次证明,这意味着FPR2/ALX调节剂而不是单独的激动剂可以改善IBD。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Acta Pharmacologica Sinica
Acta Pharmacologica Sinica 医学-化学综合
CiteScore
15.10
自引率
2.40%
发文量
4365
审稿时长
2 months
期刊介绍: APS (Acta Pharmacologica Sinica) welcomes submissions from diverse areas of pharmacology and the life sciences. While we encourage contributions across a broad spectrum, topics of particular interest include, but are not limited to: anticancer pharmacology, cardiovascular and pulmonary pharmacology, clinical pharmacology, drug discovery, gastrointestinal and hepatic pharmacology, genitourinary, renal, and endocrine pharmacology, immunopharmacology and inflammation, molecular and cellular pharmacology, neuropharmacology, pharmaceutics, and pharmacokinetics. Join us in sharing your research and insights in pharmacology and the life sciences.
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