# Roles of novel MRGPRX2/MrgprB2 signaling in mast cells on host defense and Inflammation

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $406,250

## Abstract

Summary:
 In addition to the high affinity IgE receptor (FcεRI), human connective tissue mast cells (MCTC) express
a recently described G protein coupled receptor (GPCR), known as Mas-related GPCR-X2 (MRGPRX2). Our
lab was the first to demonstrate that host defense antimicrobial peptides (HDPs) activate human mast cells
via MRGPRX2, which likely contributes to innate immunity. Emerging evidence suggests that MRGPRX2-
mediated local mast cell activation clears bacterial infection via the recruitment of neutrophils and promotes
adaptive immunity to control reinfection. However, dysregulation of host defense and excessive generation
of the host defense peptide, LL-37 contributes to the pathogenesis of rosacea. MrgprB2 is the mouse
counterpart of human MRGPRX2 and our preliminary data demonstrated that LL-37-mediated experimental
rosacea is significantly reduced in MrgprB2-/- mice when compared to wild-type mice. MRGPRX2 also serves
as a novel GPCR for neuropeptides such as substance P, hemokinin-1 and pituitary adenylate cyclase-
activating peptide (PACAP). Furthermore, MRGPRX2 is an “atypical opioid receptor” and some of the side
effects opioids are likely mediated via mast cell degranulation through this receptor. However, the molecular
mechanisms involved in the activation and regulation of its downstream signaling remains largely unknown.
 In addition to G proteins, many GPCR agonists also signal via the recruitment of adapter proteins
known as β-arrestins. This pathway not only contributes to GPCR desensitization but also provides a platform
for a variety of G protein-independent signaling. Biased GPCR agonists preferentially activate pathways
mediated by G proteins (G protein-biased) or β-arrestins (β-arrestin-biased). Agonists that activate both
pathways are known as balanced agonists. Recently, we made the surprising observation that while compound
48/80 activates both G protein and β-arrestin (balanced agonist) an angiogenic host defense peptide activates
only G protein but not β-arrestin (G protein-biased agonist). Based on these findings, we hypothesize that
balanced and G protein-biased MRGPRX2 agonists activate mast cells via different mechanisms to
promote distinct biological responses in vivo. Because MrgprB2 is the mouse counterpart of the human
MRGPRX2, we will incorporate this receptor for many of our in vivo studies. In aim #1, we will determine which
of the known mast cell secretagogues (HDPs, neuropeptides, opioids and FDA-approved pseudo-allergic
drugs) act as balanced and G protein-biased agonists for MRGPRX2. We will also identify the structural
determinants on the receptor that facilitate their coupling to G protein and β-arrestins. In aim #2, we will
modulate host defense, pseudo-allergy and rosacea by targeting MRGPRX2/MrgprB2’s balanced/G protein
biased signaling in mast cells in vivo. In aim #3, we will determine the roles of β-arrestin1 and β-arrestin2 on
MRGPRX2 and MrgprB2-mediated signaling in vitro and biological re...

## Key facts

- **NIH application ID:** 10745330
- **Project number:** 5R01AI149487-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Hydar Ali
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $406,250
- **Award type:** 5
- **Project period:** 2019-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10745330

## Citation

> US National Institutes of Health, RePORTER application 10745330, Roles of novel MRGPRX2/MrgprB2 signaling in mast cells on host defense and Inflammation (5R01AI149487-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10745330. Licensed CC0.

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