Upregulation of Mas-related G Protein coupled receptor X2 in asthmatic lung mast cells and its activation by the novel neuropeptide hemokinin-1

Abstract

Hemokinin-1 (HK-1) is a novel neuropeptide produced by human bronchial cells and macrophages and causes contraction of human bronchi ex vivo. It is also generated by antigen/IgE-activated murine mast cells (MCs) and contributes to experimental chronic allergic airway inflammation via the activation of the neurokinin receptor-1 (NK-1R) expressed on murine MCs. We found elevated MC numbers in the lungs of individuals who died from asthma (asthma) when compared to lungs of individuals who died from other causes (non-asthma). Mas-related G Protein coupled receptor X2 (MRGPRX2) is a novel G-protein coupled receptor (GPCR) that is expressed predominantly on human MCs. We detected low level of MRGPRX2 in non-asthma lung MCs but its expression was significantly upregulated in asthma lung MCs. HK-1 caused degranulation in a human MC line (LAD2) and RBL-2H3 cells stably expressing MRGPRX2 and this response was resistant to inhibition by an NK-1R antagonist. However, knockdown of MRGPRX2 in LAD2 cells resulted in substantial inhibition of HK-1-induced degranulation. These findings suggest that while HK-1 contributes to the development of experimental asthma in mice via NK-1R on murine MCs the effect of this neuropeptide on human bronchoconstriction likely reflects the activation of MRGPRX2 on lung MCs. Thus, development of selective MRGPRX2 antagonists could serve as novel target for the modulation of asthma.

MRGPRX2 is negatively targeted by SCF and IL‐4 to diminish pseudo‐allergic stimulation of skin mast cells in culture

“…Similarly, MRGPRX2 protein expression declined in vitro, but was still measurable in the majority of cases (Figure B). To assess whether reduced MRGPRX2 expression translates to functional impairment, we measured MC degranulation responses to the prototypical MGPRX2‐ligand c48/80 and found that histamine release was indeed depressed in cultured MCs, yet responses were still detectable (Figure C).…”

“…While allergic MC activation proceeds via a three component system of high affinity IgE receptor (FcεRI), allergen‐specific IgE and the matching allergen, the clinically undistinguishable pseudo‐allergic reaction requires only two components, the receptor MRGPRX2 and one of its numerous ligands, for example compound 48/80 (c48/80), Substance P (SP), other neuropeptides or drugs . Contrary to FcεRI, MRGPRX2 is mostly confined to MC TC type MCs (MCs in skin), and skin MCs were the only samples to express MRGPRX2 across the FANTOM5 atlas . MCs used for research purposes are typically expanded in culture, and this provides a different microenvironment compared to the cells’ natural habitat, inducing adaptations in the MCs .…”

Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions

“…Mast cell MRGPRX2 plays a pivotal role in mediating pseudo-allergic reactions to several FDA approved drugs (3,(19)(20)(21)(22)(23)(24) and chronic inflammation associated with asthma (18), urticaria (7), and rosacea (6). We have identified a role for SOCE via STIM1 in regulating MRGPRX2 responses in mast cells.…”

“…LL-37 expression is upregulated in patients with chronic inflammatory skin conditions such as rosacea (17), suggesting that mast cell activation via MRGPRX2 may be responsible for the symptoms associated with this disease. In addition, the pathology of several allergic diseases such as asthma (18) and urticaria (7) correlate with mast cell-specific expression of MRGPRX2. Mouse mast cells express MrgprB2, an ortholog of the human receptor (3).…”

A Novel Human MrgX2-ELISA Kit to Detect MrgX2 Concentration Associated with Chronic Urticaria

“…Allergic asthma, the most common phenotype of asthma, is clinically de ned by the presence of allergic sensitization and a correlation between asthma symptoms and allergen exposure [18,19]. MrgX2 may promote the development of asthma and may serve as a potential new target for regulating this chronic in ammatory disease [20]. MrgX2 may also be as a potential biomarker for predicting treatment outcomes in allergic asthma [21].…”