Abstract
Mas-related G-protein coupled receptor member X2 (MRGPRX2) is a class A GPCR expressed on mast cells. Mast cells are granulated tissue-resident cells known for host cell response, allergic response, and vascular homeostasis. Immunoglobulin E receptor (FcεRI)-mediated mast cell activation is a well-studied and recognized mechanism of allergy and hypersensitivity reactions. However, non-IgE-mediated mast cell activation is less explored and is not well recognized. After decades of uncertainty, MRGPRX2 was discovered as the receptor responsible for non-IgE-mediated mast cells activation. The puzzle of non-IgE-mediated pseudo-allergic reaction is unlocked by MRGPRX2, evidenced by a plethora of reported endogenous and exogenous MRGPRX2 agonists. MRGPRX2 is exclusively expressed on mast cells and exhibits varying affinity for many molecules such as antimicrobial host defense peptides, neuropeptides, and even US Food and Drug Administration-approved drugs. The discovery of MRGPRX2 has changed our understanding of mast cell biology and filled the missing link of the underlying mechanism of drug-induced MC degranulation and pseudo-allergic reactions. These non-canonical characteristics render MRGPRX2 an intriguing player in allergic diseases. In the present article, we reviewed the emerging role of MRGPRX2 as a non-IgE-mediated mechanism of mast cell activation in pseudo-allergic reactions. We have presented an overview of mast cells, their receptors, structural insight into MRGPRX2, MRGPRX2 agonists and antagonists, the crucial role of MRGPRX2 in pseudo-allergic reactions, current challenges, and the future research direction.
Highlights
The pseudo-allergic reaction is a hypersensitivity reaction manifested by immediate systemic responses
We have presented an overview of mast cells, their receptors, structural insight into MAS-Related G Protein-Coupled Receptors X 2 (MRGPRX2), MRGPRX2 agonists and antagonists, the crucial role of MRGPRX2 in pseudo-allergic reactions, current challenges, and the future research direction
We have provided a brief introduction of mast cells, their receptors, and the diverse agonists of MRGPRX2
Summary
The pseudo-allergic reaction is a hypersensitivity reaction manifested by immediate systemic responses. The symptoms are identical to anaphylaxis; pseudo-allergic reaction shares a different mechanism of mast cells (MCs) activation to that of anaphylaxis (Immunoglobulin E (IgE)-mediated) [1]. Pseudo-allergic reactions are non-IgE-mediated hypersensitivity reactions which are elicited by an initial dose of medication, and cause MC degranulation followed by the release of inflammatory and pro-inflammatory mediators [2]. MRGPRX2 is a class A GPCR which binds with several endogenous and exogenous ligands Research on both MC degranulation and host response mechanism was focused on the IgE receptors (FcεRI)-mediated immune response. MC receptor responsible for non-IgE-mediated pseudo-allergic reactions. More than 20 ligands (agonists or antagonists) have already been identified, and the quest for more agonists/antagonists that may solve the puzzle of non-IgE-mediated pseudo-allergic reactions is in full swing. More comprehensive studies and a clear understanding of MRGPRX2 pharmacology will contribute to a deeper understanding of several non-IgE-mediated pathologies and might offer new opportunities for designing novel putative treatments for several allergic and non-allergic disorders
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