REGULATION OF MRGPRX2-MEDIATED MAST CELL FUNCTIONS AND THE ROLES OF MRGPRB2 IN CUTANEOUS HOST DEFENSE

Loading...
Thumbnail Image
Degree type
Doctor of Science in Dentistry (DScD)
Graduate group
Discipline
Biology
Subject
Mast cell biology
Immunology
Host defense
Funder
Grant number
Copyright date
2023
Distributor
Related resources
Amponnawarat A, Chompunud Na Ayudhya C, Ali H. Murepavadin, a Small Molecule Host Defense Peptide Mimetic, Activates Mast Cells via MRGPRX2 and MrgprB2. Front Immunol. 2021 Jun 23;12:689410. doi: 10.3389/fimmu.2021.689410. PMID: 34248979; PMCID: PMC8261236.
https://www.frontiersin.org/articles/10.3389/fimmu.2021.689410/full
Author
Amponnawarat, Aetas
Contributor
Abstract

Mas-related G protein-coupled receptor (GPCR) X2 (MRGPRX2; mouse ortholog MRGPRB2) is expressed in mast cells (MCs). Activation of MRGPRX2/B2 by bacterial-derived competence-stimulating peptide-1 (CSP-1) promotes host defense and but its activation by proadrenomedullin N-terminal peptide 9-20 (PAMP-12), which is derived from keratinocytes, contributes to allergic contact dermatitis (ACD). Certain MRGPRX2 agonists couple only to G proteins to induce calcium mobilization and degranulation (G protein-biased agonists), whereas others activate an additional signaling pathway that involves the recruitment of β-arrestins (balanced agonists), resulting in receptor desensitization and internalization. We sought to test the hypothesis that different biological outcomes of MRGPRX2 activation by CSP-1 and PAMP-12 reflect their ability to serve as G protein-biased or balanced agonists for the receptor. We found that both PAMP-12 and CSP-1 caused MRGPRX2 to couple to the same set of G proteins to induce similar levels of degranulation. However, PAMP-12 caused β-arrestin recruitment and promoted MRGPRX2 desensitization and internalization, but CSP-1 did not. To test the possibility that β-arrestins differentially regulate MRGPRB2-mediated responses to PAMP-12 and CSP-1, we utilized primary cultures peritoneum-derived MCs (PMCs) from wild- type (WT), Arrb1−/−, and Arrb2−/− mice. Unexpectedly, we found that intracellular calcium mobilization and degranulation in response to both PAMP-12 and CSP-1 were significantly enhanced in Arrb1−/− and Arrb2−/− PMCs when compared to WT PMCs. In addition to CSPs, host-derived antimicrobial peptides (also known as Host Defense Peptides, HDPs) contribute to host defense by activating MCs via MRGPRX2. We, therefore, tested the ability of a small molecule HDP mimetic, murepavadin, to activate MCs in vitro and to promote host defense in vivo. As for CSP-1, murepavadin served as a G protein-biased agonist for MRGPRX2 to induce calcium mobilization and degranulation. Furthermore, it promoted neutrophil recruitment and facilitated Staphylococcus aureus clearance from infected paw skin in mice through the activation of MCs via MRGPRB2. This study reveals the novel findings that the ability of CSP-1 and murepavadin to serve as G protein-biased agonists for MRGPRX2 provide sufficient signals to harness MC’s immunomodulatory property for host defense, but the activation of additional β- arrestin-mediated receptor internalization signal by PAMP-12 may contribute to ACD.

Advisor
Ali, Hydar
Date of degree
2023
Date Range for Data Collection (Start Date)
Date Range for Data Collection (End Date)
Digital Object Identifier
Series name and number
Volume number
Issue number
Publisher
Publisher DOI
Journal Issue
Comments
Recommended citation