Endogenous protein and enzyme fragments induce immunoglobulin E‐independent activation of mast cells via a G protein‐coupled receptor,MRGPRX2

Abstract

Mast cells play a central role in inflammatory and allergic reactions by releasing inflammatory mediators through 2 main pathways, immunoglobulin E-dependent and E-independent activation. In the latter pathway, mast cells are activated by a diverse range of basic molecules (collectively known as basic secretagogues) through Mas-related G protein-coupled receptors (MRGPRs). In addition to the known basic secretagogues, here, we discovered several endogenous protein and enzyme fragments (such as chaperonin-10 fragment) that act as bioactive peptides and induce immunoglobulin E-independent mast cell activation via MRGPRX2 (previously known as MrgX2), leading to the degranulation of mast cells. We discuss the possibility that MRGPRX2 responds various as-yet-unidentified endogenous ligands that have specific characteristics, and propose that MRGPRX2 plays an important role in regulating inflammatory responses to endogenous harmful stimuli, such as protein breakdown products released from damaged or dying cells.

Novel MRGPRX2 antagonists inhibit IgE-independent activation of human umbilical cord blood-derived mast cells

“…Others and ours studies indicate that MRGPRs mediate the IgE‐independent activation of MCs by basic secretagogues such as SP, VIP, and PACAP (6‐27). Recently, we showed that several endogenous enzyme‐fragmented peptides (CNP fragments and chaperonin‐10 fragments) were MRGPRX2 ligands and could induce degranulation in MCs . McNeil et al.…”

“…Recently, we showed that several endogenous enzyme-fragmented peptides (CNP fragments and chaperonin-10 fragments) were MRG-PRX2 ligands and could induce degranulation in MCs. 23 McNeil et al…”

MRGPRX2 activation as a rapid, high-throughput mechanistic-based approach for detecting peptide-mediated human mast cell degranulation liabilities

“…Consequently, cell models that can quickly and accurately identify peptides with a MCD hazard early in the drug development process are highly beneficial to avoid development of peptide drugs with MCD-associated liabilities (such as anaphylactoid reactions and/or ISR). MRGPRX2 has been reported to be responsible for activation of the non-IgE peptidergic MCD pathway by a number of basic secretagogues and therapeutic drugs (McNeil et al 2015;Tatemoto et al 2018). MRGPRX2 is part of the Mas-related gene (MRG) family of GPCR that is comprised of almost 50 members divided into several subfamilies (A-H and X); the X sub-family is specific to primates, including humans, macaques, and rhesus monkeys (Solinski et al 2014).…”

Mas-related G protein–coupled receptor X2 and its activators in dermatologic allergies

“…7,[26][27][28] Thus, in contrast to the activation pattern of other GPCRs, MRGRX2 is activated by a broad range of ligands. 29,30 Unlike other GPCRs (eg, C3aR), MRGPRX2 may be resistant to phosphorylation, internalization, and desensitization following activation by certain, albeit not all, agonists. 15,31 The latter fact may explain the responsiveness of MRGPRX2 to multiple ligands.…”

“…Identification of these MC-activating protein fragments provides future opportunities in study of the role of MRGPRX2 in various inflammatory disorders. 29,191 C48/80. C48/80, which is a synthetic polymer produced by condensation of N-methyl-p-methoxy phenylethylamine with formaldehyde, has been known to activate human and rodent MCs since the early 1970s.…”