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Mas-related G protein-coupled receptor-X2 (MRGPRX2) is known as a novel receptor to activate mast cells (MCs). MRGPRX2 plays a dual role in promoting MC-dependent host defense and immunomodulation and contributing to the pathogenesis of pseudo-allergic drug reactions, pain, itching, and inflammatory diseases. In this article, we discuss the possible signaling pathways of MCs activation mediated by MRGPRX2 and summarize and classify agonists and inhibitors of MRGPRX2 in MCs activation. MRGPRX2 is a low-affinity and low-selectivity receptor, which allows it to interact with a diverse group of ligands. Diverse MRGPRX2 ligands utilize conserved residues in its transmembrane (TM) domains and carboxyl-terminus Ser/Thr residues to undergo ligand binding and G protein coupling. The coupling likely initiates phosphorylation cascades, induces Ca mobilization, and causes degranulation and generation of cytokines and chemokines via MAPK and NF-κB pathways, resulting in MCs activation. Agonists of MRGPRX2 on MCs are divided into peptides (including antimicrobial peptides, neuropeptides, MC degranulating peptides, peptide hormones) and nonpeptides (including FDA-approved drugs). Inhibitors of MRGPRX2 include non-selective GPCR inhibitors, herbal extracts, small-molecule MRGPRX2 antagonists, and DNA aptamer drugs. Screening and classifying MRGPRX2 ligands and summarizing their signaling pathways would improve our understanding of MRGPRX2-mediated physiological and pathological effects on MCs.
Learn More >Patient-Reported Outcomes Measurement Information System Global Health (PGH) was validated to assess health-related quality of life (HRQOL) in several diseases. Little is known about its measurement properties in adult atopic dermatitis (AD).
Learn More >Psoriasis and atopic dermatitis (AD) are two common chronic inflammatory skin diseases. Although showing different etiology and clinical manifestations, patients with either disease suffer from low health-related quality of life due to pruritus (dermal itch). Recent studies have revealed that more than 85% of psoriasis patients suffer from pruritus, and it is also the dominating symptom of AD. However, as this is a non-life treating symptom, it was partly neglected for years. In this review, we focus on current findings as well as the impact and potential treatments of pruritus in these two skin diseases. We first distinguish the type of itch based on involved mediators and modulators. This clear delineation between the types of pruritus based on involved receptors and pathways allows for precise treatment. In addition, insights into recent clinical trials aimed to alleviate pruritus by targeting these receptors are presented. We also report about novel advances in combinatorial treatments, dedicated to the type of pruritus linked to a causal disease. Altogether, we suggest that only a focused treatment tailored to the primary disease and the underlying molecular signals will provide fast and sustained relief of pruritus associated with psoriasis or AD.
Learn More >Lateral and ventral lateral subregions of the periaqueductal gray (l/vlPAG) have been proved to be pivotal components in descending circuitry of itch processing, and their effects are related to the subclassification of neurons that were meditated. In the present study, lateral parabrachial nucleus (LPB), one of the most crucial relay stations in the ascending pathway, was taken as the input nucleus to examine the modulatory effect of l/vlPAG neurons that received LPB projections. Anatomical tracing, chemogenetic, optogenetic and local pharmacological approaches were utilized to investigate the participation of the LPB-l/vlPAG pathway in itch and pain sensation in mice. First, morphological evidence for projections from vesicular glutamate transporter-2 (VGluT2)-containing neurons in the LPB to l/vlPAG involved in itch transmission has been provided. Furthermore, chemogenetic and optogenetic activation of the LPB-l/vlPAG pathway resulted in both antipruritic effect and analgesic effect, whereas pharmacogenetic inhibition strengthened nociceptive perception without affecting spontaneous scratching behavior. Finally, in vivo pharmacology was combined with optogenetics which revealed that AMPA receptor-expressing neurons in l/vlPAG might play a more essential role in pathway modulation. These findings provide a novel insight about the connections between two prominent transmit nuclei, LPB and l/vlPAG, in both pruriceptive and nociceptive sensations, and deepen the understanding of l/vlPAG modulatory roles in itch sensation by chosen LPB as source of ascending efferent projections.
Learn More >Prurigo nodularis (PN) is a chronic skin dermatosis with hyperkeratotic and intensely pruritic nodules. Managing PN-associated itch is difficult because its etiology is still unknown. This study aimed to investigate the correlation between itch intensity in PN and the expression of a pruritogenic cytokine interleukin (IL)-31, its receptor complex components IL-31 receptor a (IL31RA) and oncostatin M receptor b (OSMRb), and oncostatin M (OSM), which is a ligand of OSMRb, through immunofluorescence staining examination. Itch intensity in PN was closely correlated with the number of dermal IL-31(+) cells (Spearman's r = 0.551, p < 0.05), dermal IL-31RA(+) cells(r = 0.475, p < 0.05), and dermal OSM(+) cells (r = 0.505, p < 0.05). In addition, the number of dermal OSMRb(+) cells was increased in PN (t-test, p < 0.05), despite not being correlated with itch intensity (Spearman's r = 0.375, p > 0.05). Major cellular sources of dermal IL-31 were T cells (27.0% of total IL-31-expressing cells) and macrophages (35.0%), while those of OSM were mainly T cells (49.8%) and mast cells (26.8%). IL-31RA expressing dermal cells were mostly mast cells (49.3%) and macrophages (36.6%), and OSMRb were mainly expressed by macrophages (51.8%) in the dermis. These findings indicate that IL-31 (mainly from macrophages and T cells) and OSM (principally from T cells and mast cells) stimulate dermal cells expressing IL-31RA and OSMRb (e.g. macrophages), which may further promote itch and inflammation in PN. This complex dermal milieu of cell/cytokine/receptor network can be a therapeutic target for PN-associated itch.
Learn More >Chronic pruritus (CP) is a subjective symptom and it is necessary to assess its intensity with validated patient-reported outcome tools in order to allow determination of the treatment course.
Learn More >Itch is an evolutionarily conserved sensation that facilitates expulsion of pathogens and noxious stimuli from the skin. However, in organ failure, cancer, and chronic inflammatory disorders such as atopic dermatitis (AD), itch becomes chronic, intractable, and debilitating. In addition to chronic itch, patients often experience intense acute itch exacerbations. Recent discoveries have unearthed the neuroimmune circuitry of itch, leading to the development of anti-itch treatments. However, mechanisms underlying acute itch exacerbations remain overlooked. Herein, we identify that a large proportion of patients with AD harbor allergen-specific immunoglobulin E (IgE) and exhibit a propensity for acute itch flares. In mice, while allergen-provoked acute itch is mediated by the mast cell-histamine axis in steady state, AD-associated inflammation renders this pathway dispensable. Instead, a previously unrecognized basophil-leukotriene (LT) axis emerges as critical for acute itch flares. By probing fundamental itch mechanisms, our study highlights a basophil-neuronal circuit that may underlie a variety of neuroimmune processes.
Learn More >Owing to their functional diversity, the Mas-related G-protein-coupled receptor (Mrgpr) family has a role in both itch and pain modulation. While primarily linked to pruritis, Mrgprs were originally characterized in small-diameter nociceptive neurons of dorsal root ganglia (DRG) and trigeminal ganglia. This review will focus on the role Mrgpr's have in pain physiology, discussing recent discoveries as well as how Mrgpr's may provide a new target for the treatment of pathological pain.
Learn More >Atopic dermatitis (AD) and allergic asthma are complex disorders with significant public health burden. This review provides an overview of the recent developments on Mas-related G protein-coupled receptor-X2 (MRGPRX2; mouse counterpart MrgprB2) as a potential candidate to target neuro-immune interaction in AD and allergic asthma.
Learn More >The Harmonising Outcome Measures for Eczema (HOME) initiative has established a core outcome set of domains for atopic eczema (AE) clinical trials. Previous consensus meetings have agreed on preferred instruments for clinician-reported signs (Eczema Area and Severity Index, EASI) and patient-reported symptoms (Patient-Oriented Eczema Measure, POEM). This paper reports consensus decisions from the HOME VII meeting.
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