Proinflammatory chemokine CXCL14 activates MAS-related G protein-coupled receptor MRGPRX2 and its putative mouse ortholog MRGPRB2

  • Commun Biol. 2024 Jan 6;7(1):52. doi: 10.1038/s42003-023-05739-5.
Ghazl Al Hamwi  1 ,  Vigneshwaran Namasivayam  1 ,  Beatriz Büschbell  1 ,  Robin Gedschold  1 ,  Stefan Golz  2 ,  Christa E Müller  3
Affiliations
  • 1. PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
  • 2. Lead Identification & Characterization, Pharma Research and Development Center, Bayer AG, Wuppertal, Germany.
  • 3. PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany. [email protected].
PMID: 38184723 DOI: 10.1038/s42003-023-05739-5
Abstract

Patients with idiopathic pulmonary fibrosis show a strongly upregulated expression of chemokine CXCL14, whose target is still unknown. Screening of CXCL14 in a panel of human G protein-coupled receptors (GPCRs) revealed its potent and selective activation of the orphan MAS-related GPCR X2 (MRGPRX2). This receptor is expressed on mast cells and - like CXCL14 - upregulated in bronchial inflammation. CXCL14 induces robust activation of MRGPRX2 and its putative mouse ortholog MRGPRB2 in G protein-dependent and β-arrestin recruitment assays that is blocked by a selective MRGPRX2/B2 antagonist. Truncation combined with mutagenesis and computational studies identified the pharmacophoric sequence of CXCL14 and its presumed interaction with the receptor. Intriguingly, C-terminal domain sequences of CXCL14 consisting of 4 to 11 Amino acids display similar or increased potency and efficacy compared to the full CXCL14 sequence (77 Amino acids). These results provide a rational basis for the future development of potential idiopathic pulmonary fibrosis therapies.

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