Abstract
Background: Mast cells are considered an attractive therapeutic target for treating allergic diseases, and the Lyn–FcεRIβ interaction is essential for mast cell activation. This study investigated the antiallergic effect of scrodentoid A (SA) on mast cells and mast cell–mediated anaphylaxis.Methods: For in vitro experiments, mast cells were treated with SA. Cell proliferation was tested using the XTT assay. The mRNA expression of various cytokines and chemokines was measured using qPCR. The levels of histamine, eicosanoids (PGD2, LTC4), and cytokines were measured using enzyme immunoassay kits. Signaling was investigated using Western blotting and immunoprecipitation. For in vivo experiments, the antiallergic activity of SA was evaluated using two mouse models of passive anaphylaxis as passive cutaneous and systemic anaphylaxis. The mechanism was investigated through immunohistochemistry and immunofluorescence.Results: SA considerably inhibited immunoglobulin (Ig) E-mediated mast cell activation, including β-hexosaminidase release, mRNA and protein expression of various cytokines, and PGD2 and LTC4 release. Oral administration of SA effectively and dose-dependently suppressed mast cell–mediated passive cutaneous and systemic anaphylaxis. SA significantly attenuated the activation of Lyn, Syk, LAT, PLCγ, JNK, Erk1/2, and Ca2+ mobilization without Fyn, Akt, and P38 activation by blocking the Lyn–FcεRIβ interaction.Conclusions: SA suppresses mast cell–mediated allergic response by blocking the Lyn–FcεRIβ interaction in vitro and in vivo. SA may be a promising therapeutic agent for allergic and other mast cell–related diseases.
Highlights
Allergy prevalence has been increasing worldwide, which has contributed directly or indirectly to health and economic burdens [1, 2]
Before investigating the effect of scrodentoid A (SA) (Figure 1A) on mast cell activation, we examined the cytotoxicity of SA on BMMCs by using XTT assay
On investigating whether SA blocked the binding between Lyn and FcεRIβ in vivo in the passive systemic anaphylaxis (PSA) model, we found that SA significantly suppressed the binding between Lyn and FcεRIβ after exposure to the allergen for 10 min, whereas ketotifen did not (Figures 8C,D)
Summary
Allergy prevalence has been increasing worldwide, which has contributed directly or indirectly to health and economic burdens [1, 2]. Mast cells are central players in both the development and maintenance of allergic diseases. Mast cell activation releases various mediators, including preformed granule-associated chemical mediators, lipid mediators, and de novo synthesized cytokines, which are essential in allergies [3]. The signaling cascades elicited by FcεRI aggregation start with Lyn phosphorylation, which transphosphylate the immunoreceptor tyrosine-based activation motif (ITAM) within FcεRIβ and FcεRIγ. Another tyrosine kinase, Syk, is recruited and binds to phosphorylated ITAM, resulting in the phosphorylation of the adaptor proteins (LAT) and phospholipase Cγ (PLCγ). Mast cells are considered an attractive therapeutic target for treating allergic diseases, and the Lyn–FcεRIβ interaction is essential for mast cell activation. This study investigated the antiallergic effect of scrodentoid A (SA) on mast cells and mast cell–mediated anaphylaxis
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