Mas-related G protein coupled receptor-X2: A potential new target for modulating mast cell-mediated allergic and inflammatory diseases

Abstract

Mast cells (MCs) are tissue resident immune cells that are best known for their roles in allergic and inflammatory diseases. In addition to the high affinity IgE receptor (FcεRI), MCs express numerous G protein coupled receptors (GPCRs), which are the most common targets of drug therapy. Neurokinin 1 receptor (NK-1R) is expressed on MCs and contributes to IgE and non-IgE-mediated responses in mice. Although NK-1R antagonists are highly effective in modulating experimental allergic and inflammatory responses in mice they lack efficacy in humans. This article reviews recent findings that demonstrate that while neuropeptides (NPs) activate murine MCs via NK-1R and Mas related G protein coupled receptor B2 (MrgprB2), they activate human MCs via Mas-related G protein coupled receptor X2 (MRGPRX2). Interestingly, conventional NK-1R antagonists have off-target activity against mouse MrgprB2 but not human MRGPRX2. These findings suggest that the failure to translate studies with NK-1R antagonists from in vivo mouse studies to the clinic likely reflects their lack of effect on human MRGPRX2. A unique feature of MRGPRX2 that distinguishes it from other GPCRs is that it is activated by a diverse group of ligands that include; neuropeptides, cysteine proteases, antimicrobial peptides and cationic proteins released from activated eosinophils. Thus, the development of small molecule MRGPRX2-specific antagonists or neutralizing antibodies may provide new targets for the treatment of MC-mediated allergic and inflammatory diseases.

Keywords: MRGPRX2; Mast cells; MrgprB2; NK-1R; anaphylaxis; asthma.

Figure 1. Proposed model for the roles of NK-1R and MrgprB2 on neuropeptide and IgE-mediated responses in mice

SP released from nerve endings and HK-1 generated from MCs activate NK-1R and MrgprB2 on MCs to induce degranulation and TNF production. These mediators contribute to increased vascular permeability and leukocyte recruitment in (A) anaphylaxis and (B) chronic asthma. It is proposed that conventional NK-1R antagonists modulate these responses in mice by inhibiting both NK-1R and MrgprB2.

Figure 2. Proposed model for the roles of human MRGPRX2 on chronic urticaria and asthma

(A): In chronic urticaria, SP released from nerve endings activate skin MC_TC via MRGPRX2 to induce degranulation and PGD₂ production. The MC-mediated response is further amplified via MRGPRX2-mediated degranulation induced by eosinophil-derived proteins, EPO and MBP. (B): MC_TC are recruited to the lung of patients with severe asthma. FcεRI-mediated MC activation leads to the release of mediators (tryptase, histamine and leukotrienes), which stimulate the production of SP from nerve endings. Activation of MRGPRX2 on lung MC_TC by SP and EPO/MBP likely contributes to the development of severe asthma. Cathepsin S released from antigen-presenting cells may also contribute to asthma severity by activating lung MC_TC via MRGPRX2. It is proposed that human β-defensins (hBD) released from rhinovirus-activated epithelial cells, EPO/MBP from eosinophils and LL-37 from neutrophils induce mediator release from human lung MC_TC via MRGPRX2 to cause asthma exacerbation.