Roles of Mas-related G protein-coupled receptor X2 on mast cell-mediated host defense, pseudoallergic drug reactions, and chronic inflammatory diseases

Abstract

Mast cells (MCs), which are granulated tissue-resident cells of hematopoietic lineage, contribute to vascular homeostasis, innate/adaptive immunity, and wound healing. However, MCs are best known for their roles in allergic and inflammatory diseases, such as anaphylaxis, food allergy, rhinitis, itch, urticaria, atopic dermatitis, and asthma. In addition to the high-affinity IgE receptor (FcεRI), MCs express numerous G protein-coupled receptors (GPCRs), which are the largest group of membrane receptor proteins and the most common targets of drug therapy. Antimicrobial host defense peptides, neuropeptides, major basic protein, eosinophil peroxidase, and many US Food and Drug Administration-approved peptidergic drugs activate human MCs through a novel GPCR known as Mas-related G protein-coupled receptor X2 (MRGPRX2; formerly known as MrgX2). Unique features of MRGPRX2 that distinguish it from other GPCRs include their presence both on the plasma membrane and intracellular sites and their selective expression in MCs. In this article we review the possible roles of MRGPRX2 on host defense, drug-induced anaphylactoid reactions, neurogenic inflammation, pain, itch, and chronic inflammatory diseases, such as urticaria and asthma. We propose that host defense peptides that kill microbes directly and activate MCs through MRGPRX2 could serve as novel GPCR targets to modulate host defense against microbial infection. Furthermore, mAbs or small-molecule inhibitors of MRGPRX2 could be developed for the treatment of MC-dependent allergic and inflammatory disorders.

Keywords: G protein–coupled receptor; MRGPRX2; asthma; chronic urticaria; drug-induced pseudoallergy; host defense peptides; mast cells; neuropeptides.

Figure 1. Activation of MRGPRX2 on MCs by HDPs may orchestrate microbial clearance and promote wound healing

Activation of epithelial cells following microbial infection leads to the generation of hBDs which cause MC chemotaxis and degranulation via MRGPRX2. MC-derived mediators cause increased vascular permeability and promote neutrophil recruitment. LL-37 released from neutrophils also activates MRGPRX2, which enhances TLR-4 expression and causes further MC chemotaxis and degranulation. Histamine and TNF-α released from MCs activate dendritic cells (DC) leading to enhanced antigen presentation to T cells. hBDs and LL-37 produced from epithelium and neutrophil, respectively, also promote keratinocyte migration and pro-inflammatory cytokines production via the transactivation of EGFR receptor. These HDPs also activate other cell surface GPCRs and intracellular receptors (GAPDH/SQSTM1) on monocytes (Mono), and macrophages (Mac) to induce growth factor and cytokine release to promote microbial clearance and wound healing.

Figure 2. Potential roles for MC-MRGPRX2 on neurogenic inflammation, pain and itch

For neurogenic inflammation and pain, tryptase released from degranulated MCs activates protease activated receptor_-2 (PAR-2) on sensory nerve endings resulting in the release of CGRP and SP, which interact with their receptors, CGRP1 and NK1R to promote arteriolar dilation and venular permeability, respectively. SP released from sensory nerve ending and from activated MCs also acts on MCs themselves, thus promoting a vicious cycle of MC activation via MRGPRX2. Furthermore, the Ca²⁺-mediated axon potential travels orthodromically along the axon to the central nervous system ultimately resulting in pain and itch responses. HDPs activate MCs via MRGPRX2, which results in the release of IL-31. Activation DRG neuron via IL-31R leads to the generation of SP, which further activates MCs via MRGPRX2 to promote the itch response.

Figure 3. MRGPRX2 signaling in MCs

The ligands for MRGPRX2 activate pertussis toxin-dependent Gαi and pertussis toxin-independent Gαq pathways for MC responses. MCs express MRGPRX2 on the cell surface as well as intracellular sites. The extracellular receptor probably uses the Orai-1 Ca²⁺ channel and the pertussis toxin-independent Gαq pathway for MC degranulation whereas the intracellular receptor may use the Orai-2 Ca²⁺ channel to mediate MC responses. Activation of MRGPRX2 also results in Gαi-dependent production of the pruritogenic cytokine IL-31 via the MAP kinase and Akt-dependent pathways.