Resveratrol inhibits MRGPRX2-mediated mast cell activation via Nrf2 pathway

Wang, Jue; Zhang, Yongjing; Hu, Shiling; Ge, Shuai; Jia, Min; Wang, Nan

doi:10.1016/j.intimp.2021.107426

Cited by 28 publications

(32 citation statements)

References 42 publications

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“…Recently, inhibitory compounds for MRGPR2 with anti-inflammatory properties by blocking the above-mentioned MRGPRX2 downstream signaling have been reported. Resveratrol, a polyphenol found in grapes, red wine, and peanuts, increases the expression of nuclear factor erythroid-derived 2-related factor (Nrf2) and induces heme-oxygenase 1 (HO-1), which has antioxidant effects [ 149 ]. Since the Nrf2/HO-1 pathway is known to suppress NF-κB signaling downstream of MRGPRX2 [ 150 ], it may indirectly suppress MRGPRX2 activation.…”

Section: Mrgprx2 Inhibitorsmentioning

confidence: 99%

Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

Ogasawara

Noguchi

2021

Cells

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Mast cells (MCs) act as primary effectors in inflammatory and allergic reactions by releasing intracellularly-stored inflammatory mediators in diseases. The two major pathways for MC activation are known to be immunoglobulin E (IgE)-dependent and -independent. Although IgE-dependent signaling is the main pathway to MC activation, IgE-independent pathways have also been found to serve pivotal roles in the pathophysiology of various inflammatory conditions. Recent studies have shown that human and mouse MCs express several regulatory receptors such as toll-like receptors (TLRs), CD48, C300a, and GPCRs, including mas-related GPCR-X2 (MRGPRX2). MRGPRX2 has been reported as a novel GPCR that is expressed in MCs activated by basic secretagogues, neurokinin peptides, host defense antimicrobial peptides, and small molecule compounds (e.g., neuromuscular blocking agents) and leads to MC degranulation and eicosanoids release under in vitro experimental condition. Functional analyses of MRGPRX2 and Mrgprb2 (mouse ortholog) indicate that MRGPRX2 is involved in MC hypersensitivity reactions causing neuroinflammation such as postoperative pain, type 2 inflammation, non-histaminergic itch, and drug-induced anaphylactic-like reactions. In this review, we discuss the roles in innate immunity through functional studies on MRGPRX2-mediated IgE-independent MC activation and also the therapeutic potential of MRGPRX2 inhibitors on allergic and inflammatory diseases.

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Section: Mrgprx2 Inhibitorsmentioning

confidence: 99%

Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

Ogasawara

Noguchi

2021

Cells

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“…While this discussion focuses on strategies for suppressing FcεRI-mediated mast cell activation, it is of interest to note recent evidence that Nrf2 activation can also inhibit the MRFPRX2 signaling that mediates pseudo-allergic mast cell activation. 84 Another agent with the potential for inhibiting both FcεRI and MRFPRX2 signaling in mast cells is paeoniflorin, a bioactive component in peony flower extracts; the mast cell stabilizing action of this agent has been demonstrated both in mast cell cultures and in rodent allergy models. [85][86][87][88] The direct molecular target of its action in this regard has yet to be defined.…”

Section: Discussion On Nutraceutical Strategies For Mast Cell Stabilizationmentioning

confidence: 99%

Nutraceutical Aid for Allergies – Strategies for Down-Regulating Mast Cell Degranulation

McCarty¹,

Lerner²,

DiNicolantonio

et al. 2021

JAA

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Interactions of antigens with the mast cell FcεRI-IgE receptor complex induce degranulation and boost synthesis of pro-inflammatory lipid mediators and cytokines. Activation of spleen tyrosine kinase (Syk) functions as a central hub in this signaling. The tyrosine phosphatase SHP-1 opposes Syk activity; stimulation of NADPH oxidase by FcεRI activation results in the production of oxidants that reversibly inhibit SHP-1, up-regulating the signal from Syk. Activated AMPK can suppress Syk activation by the FcεRI receptor, possibly reflecting its ability to phosphorylate the FcεRI beta subunit. Cyclic GMP, via protein kinase G II, enhances the activity of SHP-1 by phosphorylating its C-terminal region; this may explain its inhibitory impact on mast cell activation. Hydrogen sulfide (H 2 S) likewise opposes mast cell activation; H 2 S can boost AMPK activity, up-regulate cGMP production, and trigger Nrf2-mediated induction of Phase 2 enzymes -including heme oxygenase-1, whose generation of bilirubin suppresses NADPH oxidase activity. Phycocyanobilin (PCB), a chemical relative of bilirubin, shares its inhibitory impact on NADPH oxidase, rationalizing reported anti-allergic effects of PCB-rich spirulina ingestion. Phase 2 inducer nutraceuticals can likewise oppose the up-regulatory impact of NADPH oxidase on FcεRI signaling. AMPK can be activated with the nutraceutical berberine. Highdose biotin can boost cGMP levels in mast cells via direct stimulation of soluble guanylate cyclase. Endogenous generation of H 2 S in mast cells can be promoted by administering N-acetylcysteine and likely by taurine, which increases the expression of H 2 S-producing enzymes in the vascular system. Mast cell stabilization by benifuuki green tea catechins may reflect the decreased surface expression of FcεRI.

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“…MRGPRX2 agonists such as human beta defensins and LL-37 have been reported to activate the MAPK/ERK, p38, and JNK pathways and increased the release of IL-31, PGE2, and leukotriene C4 [ 96 , 97 ]. A recent study reported the involvement of the Nrf2 pathway in MRGPRX2-mediated MC degranulation and pseudo-allergic reactions [ 98 ]. Indeed, more studies are warranted to understand the downstream signaling pathways of MRGPRX2.…”

Section: Pharmacology Of Mas-related G Protein-coupled Receptors X 2 (Mrgprx2)mentioning

confidence: 99%

“…Resveratrol inhibited compound 48/80-induced Ca 2+ mobilization and MC degranulation. Additionally, resveratrol demonstrated attenuation of compound 48/80-induced hind paw extravasation, and systemic anaphylaxis in mouse models [ 98 ].…”

Section: Development Of Mrgprx2 Antagonistsmentioning

confidence: 99%

Unlocking the Non-IgE-Mediated Pseudo-Allergic Reaction Puzzle with Mas-Related G-Protein Coupled Receptor Member X2 (MRGPRX2)

Kumar

Duraisamy

Chow

2021

Cells

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Mas-related G-protein coupled receptor member X2 (MRGPRX2) is a class A GPCR expressed on mast cells. Mast cells are granulated tissue-resident cells known for host cell response, allergic response, and vascular homeostasis. Immunoglobulin E receptor (FcεRI)-mediated mast cell activation is a well-studied and recognized mechanism of allergy and hypersensitivity reactions. However, non-IgE-mediated mast cell activation is less explored and is not well recognized. After decades of uncertainty, MRGPRX2 was discovered as the receptor responsible for non-IgE-mediated mast cells activation. The puzzle of non-IgE-mediated pseudo-allergic reaction is unlocked by MRGPRX2, evidenced by a plethora of reported endogenous and exogenous MRGPRX2 agonists. MRGPRX2 is exclusively expressed on mast cells and exhibits varying affinity for many molecules such as antimicrobial host defense peptides, neuropeptides, and even US Food and Drug Administration-approved drugs. The discovery of MRGPRX2 has changed our understanding of mast cell biology and filled the missing link of the underlying mechanism of drug-induced MC degranulation and pseudo-allergic reactions. These non-canonical characteristics render MRGPRX2 an intriguing player in allergic diseases. In the present article, we reviewed the emerging role of MRGPRX2 as a non-IgE-mediated mechanism of mast cell activation in pseudo-allergic reactions. We have presented an overview of mast cells, their receptors, structural insight into MRGPRX2, MRGPRX2 agonists and antagonists, the crucial role of MRGPRX2 in pseudo-allergic reactions, current challenges, and the future research direction.

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Resveratrol inhibits MRGPRX2-mediated mast cell activation via Nrf2 pathway

Cited by 28 publications

References 42 publications

Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

Nutraceutical Aid for Allergies – Strategies for Down-Regulating Mast Cell Degranulation

Unlocking the Non-IgE-Mediated Pseudo-Allergic Reaction Puzzle with Mas-Related G-Protein Coupled Receptor Member X2 (MRGPRX2)

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