LL-37-induced human mast cell activation through G protein-coupled receptor MrgX2

Yu, Yangyang; Zhang, Yuanyuan; Zhang, Yarui; Lai, Yihong; Chen, Wenwen; Xiao, Zhangang; Zhang, Wei; Jin, Meiling; Yu, Bo

doi:10.1016/j.intimp.2017.05.016

Cited by 48 publications

(27 citation statements)

References 34 publications

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“…Previous reports have established that MRGPRX2-induced mast cell activation results in downstream signaling events that activate the MAP kinase ERK1/2 (46). This signaling pathway ultimately regulate mast cell degranulation and cytokine production (47,48).…”

Section: Osthole Inhibits Chemokine/cytokine Production and Mitogen-amentioning

confidence: 97%

Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses

et al. 2020

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Mast cells are tissue-resident innate immune cells known for their prominent role in mediating allergic reactions. MAS-related G-protein coupled receptor-X2 (MRGPRX2) is a promiscuous G-protein coupled receptor (GPCR) expressed on mast cells that is activated by several ligands that share cationic and amphipathic properties. Interestingly, MRGPRX2 ligands include certain FDA-approved drugs, antimicrobial peptides, and neuropeptides. Consequently, this receptor has been implicated in causing mast cell-dependent pseudo-allergic reactions to these drugs and chronic inflammation associated with asthma, urticaria and rosacea in humans. In the current study we examined the role of osthole, a natural plant coumarin, in regulating mast cell responses when activated by the MRGPRX2 ligands, including compound 48/80, the neuropeptide substance P, and the cathelicidin LL-37. We demonstrate that osthole attenuates both the early (Ca 2+ mobilization and degranulation) and delayed events (chemokine/cytokine production) of mast cell activation via MRGPRX2 in vitro. Osthole also inhibits MrgprB2-(mouse ortholog of human MRGPRX2) dependent inflammation in in vivo mouse models of pseudo-allergy. Molecular docking analysis suggests that osthole does not compete with the MRGPRX2 ligands for interaction with the receptor, but rather regulates MRGPRX2 activation via allosteric modifications. Furthermore, flow cytometry and confocal microscopy experiments reveal that osthole reduces both surface and intracellular expression levels of MRGPRX2 in mast cells. Collectively, our data demonstrate that osthole inhibits MRGPRX2/MrgprB2-induced mast cell responses and provides a rationale for the use of this natural compound as a safer alternative treatment for pseudo-allergic reactions in humans.

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Section: Osthole Inhibits Chemokine/cytokine Production and Mitogen-amentioning

confidence: 97%

Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses

et al. 2020

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“…MCs can be activated by peptides derived from endogenous and exogenous sources[37–39]. LL-37, which is found within leukocytes and several tissues and bodily fluids in humans[40], binds human MCs through the MRGPRX2 receptor triggering degranulation and de novo secretion of cytokines, such as IL-8[37]. The adjuvant activity of LL-37 was demonstrated using an oral vaccine against Dengue virus[41].…”

Section: Vaccine Adjuvant Activity Of Mast Cell Activators (Mca)mentioning

confidence: 99%

Mast cell activators as novel immune regulators

Johnson‐Weaver

Choi

Abraham

et al. 2018

Current Opinion in Pharmacology

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Mast cells are an important cell type of the innate immune system that when activated, play a crucial role in generating protective innate host responses after bacterial and viral infection. Additionally, activated mast cells influence lymph node composition to regulate the induction of adaptive immune responses. The recognition that mast cells play a beneficial role in host responses to microbial infection and induction of adaptive immunity has provided the rationale to evaluate mast cell activators for use as antimicrobials or vaccine adjuvants. This review summarizes the role of mast cell activators in antimicrobial responses while also discussing the use of different classes of mast cell activators as potent vaccine adjuvants that enhance the induction of protective immune responses.

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“…MRGPRX2 displays a promiscuous ligand-binding domain that is potently activated by a variety of different cationic peptides and chemical effectors (10)(11)(12)(13). The cathelicidin peptide LL-37 (13,14), neuropeptide cortistatin-14 (CST-14) (10,15), and mast cell-degranulating molecule compound 48/80 (3,16) especially, produce robust degranulation responses through MRGPRX2. LL-37 expression is upregulated in patients with chronic inflammatory skin conditions such as rosacea (17), suggesting that mast cell activation via MRGPRX2 may be responsible for the symptoms associated with this disease.…”

Section: Introductionmentioning

confidence: 99%

Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions

et al. 2020

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Mast cells are inflammatory immune cells that play an essential role in mediating allergic reactions in humans. It is well-known that mast cell activation is critically regulated by intracellular calcium ion (Ca 2+) concentrations. MAS-related G-protein coupled receptor-X2 (MRGPRX2) is a G-protein coupled receptor (GPCR) expressed on mast cells that is activated by various ligands, including several FDA approved drugs; consequently, this receptor has been implicated in causing pseudo-allergic reactions in humans. MRGPRX2 activation leads to an increase in intracellular Ca 2+ levels; however, the Ca 2+ mobilizing mechanisms utilized by this receptor are largely unknown. Previous reports showed that store-operated Ca 2+ entry (SOCE) via the calcium sensor, stromal interaction molecule 1 (STIM1), regulates mast cell response induced by the high-affinity IgE receptor (FcεRI). In this study, using complementary pharmacologic and genetic ablation approaches we demonstrate that SOCE through STIM1 promotes MRGPRX2-induced human mast cell response in vitro. Importantly, SOCE also critically modulates MrgprB2 (mouse ortholog of human MRGPRX2) dependent inflammation in in vivo mouse models of pseudo-allergy. Collectively, our data suggests that MRGPRX2/MrgprB2 activation of mast cells is dependent on SOCE via STIM1, and further characterization of the MRGPRX2-SOCE-STIM1 pathway will lead to the identification of novel targets for the treatment of pseudo-allergic reactions in humans.

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LL-37-induced human mast cell activation through G protein-coupled receptor MrgX2

Cited by 48 publications

References 34 publications

Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses

Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses

Mast cell activators as novel immune regulators

Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions

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