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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Inflammation
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1433982

Pharmacological blockade of the mast cell MRGPRX2 receptor supports investigation of its relevance in skin disorders

Provisionally accepted
Colin H. Macphee Colin H. Macphee 1Xinzhong Dong Xinzhong Dong 2Qi Peng Qi Peng 2Daniel V. Paone Daniel V. Paone 1Per S. Skov Per S. Skov 3Katrine Baumann Katrine Baumann 3Theresa J. Roethke Theresa J. Roethke 1Deborah A. Goldspink Deborah A. Goldspink 4Samuel X. Pearson Samuel X. Pearson 4Zining Wu Zining Wu 1*
  • 1 GlaxoSmithKline (United States), Philadelphia, United States
  • 2 Johns Hopkins Medicine, Johns Hopkins University, Baltimore, Maryland, United States
  • 3 RefLab ApS, Kanalholmen, Denmark
  • 4 GlaxoSmithKline (United Kingdom), Brentford, England, United Kingdom

The final, formatted version of the article will be published soon.

    Introduction: Since MRGPRX2 is now recognized as the mast cell receptor for basic secretagogues, there's currently tremendous interest in whether MRGRPX2 could play an important role in various pruritic dermatoses such as chronic spontaneous urticaria. We therefore sought to identify new potent and selective antagonists to pharmacologically characterize the biological role of MRGPRX2.Methods: Various relevant in vitro, ex vivo and in vivo model systems were used to investigate the role of MRGPRX2. This included the study of freshly isolated human skin mast cells and human basophils as well as an ex vivo human skin microdialysis preparation. The additivity of MRGPRX2 and FcR1 mediated degranulation was also investigated. Human MRGPRX2 knock-in mice were generated to interrogate pharmacokinetic/pharmacodynamic (PK/PD) relationships since both antagonists studied were shown to be human specific.Results: Two novel and structurally distinct MRGPRX2 antagonists were identified with one, compound B, being orally active and demonstrating high potency in blocking Substance Pmediated degranulation using freshly isolated human skin mast cells (IC50 = 0.42 nM). Compound B also potently blocked Substance Pstimulated histamine release from resident mast cells in a human skin explant setup as well as blocking itch in an established behavioral scratching model using MRGPRX2 knock-in mice. Unlike human mast cells, Substance P failed to elicit a functional response in human basophils.These data fully support the investigation of MRGPRX2 receptor antagonists in mast cell driven allergic skin disorders such as chronic spontaneous urticaria.

    Keywords: mast cell, MRGPRX2, Skin, Neuropeptides, Substance P, antagonist

    Received: 16 May 2024; Accepted: 18 Sep 2024.

    Copyright: © 2024 Macphee, Dong, Peng, Paone, Skov, Baumann, Roethke, Goldspink, Pearson and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Zining Wu, GlaxoSmithKline (United States), Philadelphia, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.