Inhibition of Mast Cell Degranulation in Atopic Dermatitis by Celastrol through Suppressing MRGPRX2

Abstract

Background. Atopic dermatitis is a common dermatological disease, and mast cell degranulation is believed to be related with the progression of atopic dermatitis. Mas-related G protein-coupled receptor-X2 (MRGPRX2), and calcium release-activated calcium channel protein 1-2 (ORAI-1, ORAI-2) are involved in mast cell degranulation. Celastrol is an active monomer of Tripterygium wilfordii, and it presents an antiatopic role. Methods. 2,4-Dinitrofluorobenzene (DNFB) and compound 48/80 (C 48/80) were used to establish a slow and acute scratching animal model, respectively. Hematoxylin-eosin and toluidine blue staining was used to investigate tissue injury. Inflammatory factor concentration was measured with ELISA. The expression of MRGPRX2, ORAI-1, and ORAI-2 was detected with immunohistochemistry (IHC) staining. Gene expression profiling and microRNA array were performed to investigate gene differential expression. Results. Celastrol greatly inhibited atopic dermatitis-related tissues injury, mast cell production, histamine release, scratching level, inflammatory factor expression, and activation of MRGPRX2/ORAI axis in the DNFB-induced atopic dermatitis model. The influence of Celastrol on atopic dermatitis was remarkably reversed by overexpression of MRGPRX2. Conclusion. We found that the improvements of atopic dermatitis caused by Celastrol were reversed by treatment with MRGPRX2OE, indicating that Celastrol might affect atopic dermatitis through MRGPRX2. This study might provide a novel thought for the prevention and treatment of atopic dermatitis by regulating MRGPRX2.

Beyond Allergies—Updates on The Role of Mas-Related G-Protein-Coupled Receptor X2 in Chronic Urticaria and Atopic Dermatitis

“…Bawazir et al [79] presented C9 as a potent and, importantly, selective inhibitor of only MRGPRX2-mediated MC degranulation. Yao C et al [80] found that the improvements of AD caused by Celastrol were reversed by means of treatment with MRGPRX2 overexpression, indicating that Celastrol might affect AD via MRGPRX2. Clarithromycin already showed positive outcomes in a preliminary clinical trial in the treatment of CU.…”

“…Several compounds of plant origin have surfaced as MRGPRX2 inhibitory agents. Celastrol [80], for instance, has exhibited MRGPRX2 inhibition and has been shown to reduce MC production, histamine release, scratching levels, and inflammatory factor expression in mice. The inhibitory effect of Celastrol was reversed upon the overexpression of MRGPRX2 in a mouse model, supporting the notion that this effect may be mediated via MRGPRX2 rather than its orthologs [80].…”

“…Celastrol [80], for instance, has exhibited MRGPRX2 inhibition and has been shown to reduce MC production, histamine release, scratching levels, and inflammatory factor expression in mice. The inhibitory effect of Celastrol was reversed upon the overexpression of MRGPRX2 in a mouse model, supporting the notion that this effect may be mediated via MRGPRX2 rather than its orthologs [80]. In very high concentrations, Osthole, an aromatic compound, has displayed inhibitory effects on MGRPRX2 in two in vitro models (LAD2 cells and RBL-2H3 cells steadily expressing MRGPRX2), in MCs isolated from human skin tissue, and in vivo in a mouse model [81].…”

“…Cells 2024, 13, x FOR PEER REVIEW 5 of 12 via MRGPRX2 rather than its orthologs [80]. In very high concentrations, Osthole, an aromatic compound, has displayed inhibitory effects on MGRPRX2 in two in vitro models (LAD2 cells and RBL-2H3 cells steadily expressing MRGPRX2), in MCs isolated from human skin tissue, and in vivo in a mouse model [81].…”

Modulation of the Mas-Related G Protein-Coupled Receptor X2 (MRGPRX2) by Xenobiotic Compounds and Its Relevance to Human Diseases

“…Exogenous ligands of MRGPRX2 include the cationic polymer compound 48/80 (C48/80), which is commonly used in receptor functional assays, and a variety of drugs approved by the Food and Drug Administration (FDA), such as fluoroquinolones (e.g., ciprofloxacin), neuromuscular blocking agents (e.g., rocuronium, atracurium), opioids (e.g., morphine), and many others [ 4 , 9 , 28 ]. MRGPRX2 can also be activated or inhibited by other exogenous agents, such as bacterial quorum sensing proteins, insect venoms [ 3 , 29 , 30 ], or many different plant xenobiotics ( Figure 1 ) [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ]; representatives of which are described in the following part of this review.…”