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

Acta Pharmacol Sin. 2025 Jul;46(7):1958-1973. doi: 10.1038/s41401-025-01525-7. Epub 2025 Mar 11.

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.

Keywords: FPR2/ALX; IBD; Quin-C1; Quin-C7; macrophages; neutrophils.

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents* / administration & dosage
  • Anti-Inflammatory Agents* / pharmacology
  • Anti-Inflammatory Agents* / therapeutic use
  • Colitis* / chemically induced
  • Colitis* / drug therapy
  • Colitis* / pathology
  • Dextran Sulfate
  • Disease Models, Animal
  • Humans
  • Inflammation / drug therapy
  • Inflammatory Bowel Diseases* / chemically induced
  • Inflammatory Bowel Diseases* / drug therapy
  • Inflammatory Bowel Diseases* / metabolism
  • Inflammatory Bowel Diseases* / pathology
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Myeloid Cells* / drug effects
  • Myeloid Cells* / metabolism
  • Receptors, Formyl Peptide* / agonists
  • Receptors, Formyl Peptide* / antagonists & inhibitors
  • Receptors, Formyl Peptide* / metabolism
  • Receptors, Lipoxin* / agonists
  • Receptors, Lipoxin* / antagonists & inhibitors
  • Receptors, Lipoxin* / metabolism

Substances

  • Receptors, Formyl Peptide
  • formyl peptide receptor 2, mouse
  • Dextran Sulfate
  • Receptors, Lipoxin
  • Anti-Inflammatory Agents