MRGPRX2 signals its importance in cutaneous mast cell biology: Does MRGPRX2 connect mast cells and atopic dermatitis?

Abstract

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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

“…TSLP, mostly expressed by epithelial cells, is considered a Th2-promoting master switch implicated in Th2-dominated pathologies in the skin, lung and other organs, and is therefore a focus in allergy-related research [ 35 , 39 , 68 , 69 , 70 , 71 , 72 ]. Considering this intimate relation and the assumption of MRGPRX2 being a key structure in AD [ 9 ], we hypothesized that TSLP may constitute one of the factors promoting the MRGPRX2 route, and found that this is indeed the case.…”

“…These include injection-site hypersensitivity, red man syndrome, and anaphylactic reactions to an array of drugs (e.g., muscle relaxants, opiates, and antibiotics) [ 4 , 6 , 8 , 13 , 16 , 92 ]. In addition to these acute responses, MRGPRX2 also contributes to complex chronic diseases of the skin, including chronic idiopathic urticaria (CIU) and AD [ 4 , 6 , 9 ]. Regarding CIU, it was reported that urticaria patients are characterized by overexpression of MRGPRX2 [ 20 ], while a newer publication confirmed this by also showing enhanced skin reactivity of patients to MRGPRX2 drug ligands [ 93 ].…”

“…The current study provides evidence that TSLP additionally promotes activation via the MRGPRX2-route. This is notable because despite the wide appreciation of MCs’ crucial part in AD pathology, it is still unresolved how exactly the cells are activated in skin lesions to initiate or perpetuate the disease [ 48 ], yet evidence is growing that MRGPRX2 may constitute a missing link at least in selected AD endotypes [ 9 ]. This is further underlined by the bidirectional crosstalk between MCs and sensory neurons in AD pathology [ 95 ], while MRGPRX2 happens to be the major MC-expressed receptor for neuropeptides like SP, vasoactive intestinal peptide (VIP), somatostatin, cortistatin, and Pituitary adenylate cyclase-activating peptide (PACAP) [ 3 , 6 ].…”

“…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 ]. In fact, the receptor is now widely believed to constitute a major participant in drug-induced pseudo-allergic/anaphylactoid phenomena and in MC-dependent diseases triggered by exogenous or endogenous neuro-, host defense, and other peptides [ 4 , 6 , 15 , 16 ].…”

“…TSLP, cutaneous MCs, FcεRI and, more recently, MRGPRX2 have all been linked to AD pathogenesis [ 9 , 36 , 48 ], and we theorized that these elements may be inter-connected. We now report that TSLP can indeed modulate the secretory competence of skin MCs.…”