MRGPRX2 Is the Codeine Receptor of Human Skin Mast Cells: Desensitization through β-Arrestin and Lack of Correlation with the FcεRI Pathway

Babina, Magda; Wang, Zhao; Roy, Saptarshi; Guhl, Sven; Franke, Kristin; Artuc, Metin; Ali, Hydar; Zuberbier, Torsten

doi:10.1016/j.jid.2020.09.017

Cited by 47 publications

(55 citation statements)

References 77 publications

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“…Degranulation is accompanied by transient detection of granule markers at the cell surface as a result of granule-plasma membrane fusion, whereby CD107a best distinguishes activated from non-activated MCs, which are visible as two clearly separated populations [ 5 , 55 ] and it was also recently used to establish a pre-diagnostic MC activation test [ 61 ].…”

Section: Resultsmentioning

confidence: 99%

“…The HRA was performed according to a method routinely employed in our laboratory [ 5 , 53 ]. In brief, MCs in PAG-CM buffer (Piperazine-N,N-bis [2-ethanesulfonic acid]-Albumin-Glucose buffer containing 3 mM CaCl2 and 1.5 mM MgCl2, pH 7.4) were stimulated by FcεRI-aggregation (anti-AER-37 antibody at 0.2 µg/mL eBioscience, San Diego, CA, USA), or c48/80 (Sigma, at 10 µg/mL), or Substance P (SP) (Bachem, Budendorf, Switzerland at 30 µM), or no stimulus (spontaneous) for 30 min at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

“…Flow-cytometric detection of CD107a cell surface expression was as described [ 5 , 55 ]. In brief, MCs were pre-stimulated with or without TSLP (7.5 ng/mL) for 30 min, then subjected to 0.2 µg/mL FcεRI-aggregation (anti-AER-37 antibody for 15 min, 30 min, 60 min), 10 µg/mL c48/80 or 30 µM SP (for 2 min and 8 min), or no stimulus (control).…”

Section: Methodsmentioning

confidence: 99%

“…MRGPRX2 cell surface staining was performed according to established protocols [ 5 , 28 ]. In brief, cells were blocked for 15 min with human AB-serum, incubated with anti-human MRGPRX2 (clone K125H4, Biolegend, 0.15 µg/mL) or isotype mouse IgG2b-PE (clone eBMG2b, eBioscience) for 30 min at 4 °C, and analyzed as above.…”

Section: Methodsmentioning

confidence: 99%

“…Clinically relevant MC activation can be evoked by the allergic route involving FcεRI, IgE, and allergen, or by the more recently discovered MAS-related G protein coupled receptor-X2 (MRGPRX2)-dependent pathway. The latter receptor can be activated by a wide range of agonists, including neuropeptides (e.g., Substance P) and exogenous substances (like compound 48/80, antibiotics, opiates) [ 3 , 4 , 5 , 6 , 7 , 8 ]. The efficient triggering of MC degranulation and the large number of ligands have moved MRGPRX2 to the center of attention in recent years [ 9 , 10 , 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Thymic Stromal Lymphopoietin Promotes MRGPRX2-Triggered Degranulation of Skin Mast Cells in a STAT5-Dependent Manner with Further Support from JNK

Babina

Wang

Franke

et al. 2021

Cells

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Thymic stromal lymphopoietin (TSLP) is released by epithelial cells following disturbed homeostasis to act as “alarmin” and driver of Th2-immunity. Aberrant TSLP expression is a hallmark of atopic diseases, including atopic dermatitis (AD). Mast cells (MCs) are overabundant in AD lesions and show signs of degranulation, but it remains unknown whether TSLP contributes to granule discharge. Degranulation of skin MCs proceeds via two major routes, i.e., FcεRI-dependent (allergic) and MRGPRX2-mediated (pseudo-allergic/neurogenic). Evidence is accumulating that MRGPRX2 may be crucial in the context of skin diseases, including eczema. The current study reveals TSLP as a novel priming factor of human skin MCs. Interestingly, TSLP selectively cooperates with MRGPRX2 to support granule discharge, while it does not impact spontaneous or FcεRI-driven exocytosis. TSLP-assisted histamine liberation triggered by compound 48/80 or Substance P, two canonical MRGPRX2 agonists, was accompanied by an increase in CD107a+ cells (a MC activation marker). The latter process was less potent, however, and detectable only at the later of two time points, suggesting TSLP may prolong opening of the granules. Mechanistically, TSLP elicited phosphorylation of STAT5 and JNK in skin MCs and the reinforced degranulation critically depended on STAT5 activity, while JNK had a contributory role. Results from pharmacological inhibition were confirmed by RNA-interference, whereby silencing of STAT5 completely abolished the priming effect of TSLP on MRGPRX2-mediated degranulation. Collectively, TSLP is the first factor to favor MRGPRX2- over FcεRI-triggered MC activation. The relevance of TSLP, MCs and MRGPRX2 to pruritis and atopic skin pathology indicates broad repercussions of the identified connection.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Thymic Stromal Lymphopoietin Promotes MRGPRX2-Triggered Degranulation of Skin Mast Cells in a STAT5-Dependent Manner with Further Support from JNK

Babina

Wang

Franke

et al. 2021

Cells

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Opioids and the Immune System

González-Espinosa

Madera-Salcedo

Molina-Martínez

et al. 2022

Opioids

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Mast Cells and Mas-related G Protein-coupled Receptor X2: Itching for Novel Pathophysiological Insights to Clinical Relevance

Castells,

Madden,

Oskeritzian

2024

Curr Allergy Asthma Rep

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Purpose of Review Clinical interest in non-IgE activation of mast cells has been growing since the description of the human MRGPRX2 receptor. Its participation in many allergic and inflammatory conditions such as non histaminergic itch, urticaria, asthma and drug hypersensitivity has been growing. We present here an updated review of its structure, expression and biology to help understand conditions and diseases attributed to its activation and/or overpexression and the search for agonists and antagonists of clinical utility. Recent Findings The description of patients presenting anaphylaxis when exposed to one or multiple MRGPRX2 agonists such as general anesthetics, antibiotics, opiods and other agents has provided evidence of potential heterogeneity in humans. Summary This review provides the most recent developments into the receptor structure, tissue expression and signaling pathways including the potential enhancement of IgE-mediated mast cell activation. New insight into its agonists and antagonists is described and future developments to adress its modulations.

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MRGPRX2 Is the Codeine Receptor of Human Skin Mast Cells: Desensitization through β-Arrestin and Lack of Correlation with the FcεRI Pathway

Cited by 47 publications

References 77 publications

Thymic Stromal Lymphopoietin Promotes MRGPRX2-Triggered Degranulation of Skin Mast Cells in a STAT5-Dependent Manner with Further Support from JNK

Thymic Stromal Lymphopoietin Promotes MRGPRX2-Triggered Degranulation of Skin Mast Cells in a STAT5-Dependent Manner with Further Support from JNK

Opioids and the Immune System

Mast Cells and Mas-related G Protein-coupled Receptor X2: Itching for Novel Pathophysiological Insights to Clinical Relevance

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