Differential Ca2+ mobilization and mast cell degranulation by FcεRI- and GPCR-mediated signaling

Chen, Ying‐Chi; Chang, Yu Chung; Chang, Heng; Lin, Yu Shan; Tsao, Chiung Wen; Shen, Meng‐Ru; Chiu, Wen Tai

doi:10.1016/j.ceca.2017.08.002

Cited by 36 publications

(25 citation statements)

References 44 publications

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“…We tested tozasertib effects on two modes of activation of mast cells, which act as effector cells in the development of allergic responses: IgE/Ag stimulation or PMACI induction (Theoharides & Kalogeromitros, 2006). IgE/Ag stimulation involves IgE cross‐linking with FcεRI cell surface receptors (Peavy & Metcalfe, 2008), whereas PAMCI induction involves activation of cell surface GPCRs and consequent influx of calcium, which activates downstream signalling (Chen et al, 2017). Both methods induced mast cell degranulation, as shown by the release of histamine and β‐hexosaminidase.…”

Section: Discussionmentioning

confidence: 99%

Aurora kinase inhibitor tozasertib suppresses mast cell activation in vitro and in vivo

Zhang

Sun

et al. 2020

British J Pharmacology

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Background and Purpose: Mast cells are important in allergic reactions. Here, we assessed the anti-allergic effects of the anti-cancer drug tozasertib specifically regarding regulatory effects on mast cell activation. Experimental Approach: Tozasertib effects on mast cell degranulation were determined by measuring β-hexosaminidase and histamine release and by assessing morphological changes in RBL-2H3 and mouse bone marrow-derived mast cells (BMMCs) stimulated with mouse anti-dinitrophenyl (DNP)-IgE/DNP-human serum albumin or human LAD2 cells activated with phorbol-12-myristate 13-acetate plus calcium ionophore (PMACI). Western blots were performed to detect the expression of molecules involved in NF-κB, MAPK, and Aurora kinase signalling. in vivo antiallergic effects of tozasertib were determined in the murine IgE-mediated passive cutaneous anaphylaxis (PCA) and ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) models. Key Results: Tozasertib treatment decreased high-affinity IgE receptor (FcεRI) or PMACI-mediated degranulation in RBL-2H3 cells and in BMMCs or LAD2 cells as shown by β-hexosaminidase or histamine levels. Similarly, tozasertib prevented morphological changes in mast cells, such as particle release and F-actin reorganization. In addition, tozasertib markedly decreased expression of phosphorylated (p)-NF-κB p65, p-Erk1/2, p-p38, and p-Aurora A/B, indicating that tozasertib can inhibit the signalling pathway mediating mast cell activation. Tozasertib attenuated IgE/Ag-induced PCA dose-dependently, as shown by reduced Evans blue staining. Similarly, tozasertib reduced body temperature levels and serum histamine levels in OVAchallenged ASA mice. Conclusion and Implications:The Aurora kinase inhibitor tozasertib suppressed mast cell activation in vitro and in vivo. Tozasertib may be a potential drug, targeting mast cell activation, to treat allergic diseases or mastocytosis.

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Section: Discussionmentioning

confidence: 99%

Aurora kinase inhibitor tozasertib suppresses mast cell activation in vitro and in vivo

Zhang

Sun

et al. 2020

British J Pharmacology

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“…Contact between the agonist and the receptor triggers complex chain reactions which, via the activation of numerous enzymes and the increase in the concentration of H + and cytosolic Ca 2+ (respectively [H + ]c and [Ca 2+ ]c), culminates with degranulation, by the exocytotic secretion of allergic mediators and the onset of an acute allergic response. The responses of the various agonist/receptor couples may differ 63,71,78 , but depend in each case on the concentration and affinity of the agonist 68 and the fundamental steps in the basic biochemical mechanism of allergic reactions do not vary ( Fig. 1):…”

Section: Physio-pathological Effects Of Cellular Acidification In Epimentioning

confidence: 99%

Acids Can Promote the Onset and Multimorbidity of Allergic and Nonallergic Airway Diseases

Molinari¹,

Molinari²,

Nervo³

2019

Preprint

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Inflammatory allergic and nonallergic respiratory pathologies often co-exist. The root cause is not clear. This paper demonstrates that it is ascribable to protons (H+) released into cells by exogenous and endogenous acids. The hypothesis of acids as the common cause stems from two considerations: a) it has long been known that exogenous acids present in air pollutants can induce the irritation of epithelial surfaces, particularly the airways, inflammation and bronchospasm; b) according to recent articles, endogenous acids, generated in cells by phospholipases, play a key role in the biochemical mechanisms of initiation and progression of allergic responses. Therefore, the intracellular acidification and consequent Ca2+ increase, induced by protons generated by either acid pollutants or endogenous phospholipases, may be the causal mechanism of the multimorbidity of these diseases, and environmental acidity may contribute to their spread.

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“…Since the Ca 2+ -mobilizing machinery utilized by MRGPRX2 in mast cells is unknown, we sought to characterize the Ca 2+ signaling responses and the proteins involved in MRGPRX2 Ca 2+ potentiation. Previous studies have demonstrated that FcεRI signaling is largely dependent upon SOCE via STIM1 to facilitate proper mast cell function (29,(32)(33)(34)(35). Given the potent inflammatory properties of the IgE receptor and MRGPRX2, in conjunction with their analogous Ca 2+ mobilization responses, we hypothesized that MRGPRX2 activates SOCE through STIM1.…”

Section: Introductionmentioning

confidence: 98%

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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Differential Ca2+ mobilization and mast cell degranulation by FcεRI- and GPCR-mediated signaling

Cited by 36 publications

References 44 publications

Aurora kinase inhibitor tozasertib suppresses mast cell activation in vitro and in vivo

Aurora kinase inhibitor tozasertib suppresses mast cell activation in vitro and in vivo

Acids Can Promote the Onset and Multimorbidity of Allergic and Nonallergic Airway Diseases

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

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