Activation of Mast-Cell-Expressed Mas-Related G-Protein-Coupled Receptors Drives Non-histaminergic Itch

Zhang

et al. 2019

Phytotherapy Research

Mas-related G protein-coupled receptor-X2 (MRGPRX2) expressed on mast cells (MCs) has been shown to be a pivotal target for pseudo-allergic diseases. Therefore, MRGPRX2 might be a therapeutic target for allergic contact dermatitis, atopic dermatitis, and red man syndrome. Paeoniflorin (PF) was reported to have an antiinflammatory effect in neuroinflammation, enteritis, and so forth. In this study, we investigated the anti-pseudo-allergic effect of PF and the underlying molecular mechanisms. Our results showed that PF can suppress compound 48/80 (C48/80)-induced PCA and MCs degranulation in vivo, in a dose-dependent manner. Moreover, PF can reduce C48/80-induced calcium influx and suppress MC degranulation and chemokines release in vitro. PF can downregulate the phosphorylation levels of key kinases in PLCγ-regulated calcium influx and subsequent cytokine synthesis pathways. Our study revealed that PF could inhibit C48/80-induced allergic responses both in vivo and in vitro. As such, it may be regarded as a novel inhibitor for preventing MRGPRX2mediated allergic diseases.

Section: Introductionmentioning

confidence: 94%

Paeoniflorin inhibits MRGPRX2‐mediated pseudo‐allergic reaction via calcium signaling pathway

Zhang

et al. 2019

Phytotherapy Research

“…Indeed, the MRGPR family plays a major role in neuronal itch sensing, with MRGPRA3 mediating chloroquine induced itch and MRGPRA1 mediating bilirubin 5 induced itch (Liu et al, 2009;Meixiong et al, 2019b). MRGPRs are expressed on both mast cells and sensory neurons, permitting these cells to directly communicate through the release of preformed mediators including neuropeptides to promote itch and allergic inflammation (Meixiong et al, 2019a;Serhan et al, 2019). Here we find that CD301b + DCs express MRGPRA1, but not other Substance P receptors, which allows these Th2-10…”

mentioning

confidence: 69%

“…At the same time, Substance P can directly activate sensory neurons, potentially boosting any response induced by direct neuronal activation (Azimi et al, 2017). Conversely, mast cell degranulation products such as trypsin can activate local sensory neurons leading to non-histaminergic itch (Meixiong et al, 2019a). To investigate the role of neuronal versus mast cell function in allergen-induced Substance P release, we first examined 5 whether inhibiting neuronal activation altered Substance P release.…”

Section: Mast Cells and Sensory Neurons Interact And Can Promote Eachmentioning

confidence: 99%

Allergen-induced dendritic cell migration is controlled through Substance P release by sensory neurons

Aderhold

Dewan

Perner

et al. 2020

Preprint

Dendritic cells (DCs) of the cDC2 lineage are necessary for the initiation of the allergic immune response and in the dermis are marked by their expression of CD301b.CD301b + dermal DCs respond to allergens encountered in vivo, but not in vitro. This suggests that another cell in the dermis may sense allergens and relay that information 5 to activate and induce the migration of CD301b + DCs to the draining lymph node. Using a model of cutaneous allergen exposure, we show that allergens directly activate TRPV1 + sensory neurons leading to itch and pain behaviors. Allergen-activated sensory neurons release the neuropeptide Substance P, which stimulates proximally located CD301b + DCs through MRGPRA1. Substance P induces CD301b + DC migration to the 10 draining lymph node where they initiate Th2 differentiation. Thus, sensory neurons act as primary sensors of allergens, linking exposure to activation of allergic-skewing DCs and the initiation of the allergic immune response. 15

Journal of Allergy and Clinical Immunology

“…24 Furthermore, recent seminal work uncovering the role of Mrgprb2 as a key receptor that mediates IgE-independent mast cell activation suggests that other modalities can also be important in mediating urticarial itch. [25][26][27] However, future studies will be required to determine the precise role of Mrgprb2 in patients with urticaria and CSU.…”

Section: Chronic Spontaneous Urticariamentioning

confidence: 99%

“…Strikingly, ACD-associated itch was dependent on Mrgprb2 across multiple models of ACD in mice. 26 Along these lines, Solinski et al 70 recently showed that chemogenetic activation of mast cells results in the release of serotonin, leukotriene C 4 , and sphingosine-1-phosphate. Notably, Nppb neurons were found to express receptors for these molecules, which activate itch along the gastrin-releasing peptide-spinal cord pathway.…”

Section: Allergic Contact Dermatitismentioning

confidence: 99%

Pruritus in allergy and immunology

Yang

Kim

2019

Self Cite

Although evolutionarily conserved to expel ectoparasites and aid in the clearance of toxins and noxious environmental stimuli from the host, the type 2 immune response can become pathologic in the setting of a variety of allergic disorders. Itch can be a behavioral extension of type 2 immunity by evoking scratching and, in the setting of disease, can become chronic and thus highly pathologic as well. Classically, our understanding of itch mechanisms has centered around the canonical IgE-mast cell-histamine axis. However, therapies aimed at blocking the histaminergic itch pathway have been largely ineffective, suggesting the existence of nonhistaminergic itch pathways.Indeed, recent advances in itch biology have provided critical new insight into a variety of novel therapeutic avenues for chronic itch in the setting of a number of allergic disorders. Here we highlight how these new developments will likely inform the problem of pruritus in a variety of well-established and emerging conditions in the field of allergy. (J Allergy Clin Immunol 2019;144:353-60.)