Dual effect of tacrolimus on mast cell–mediated allergy and inflammation through Mas-related G protein-coupled receptor X2

Xueshan Du , Delu Che , Bin Peng , Yi Zheng , Yong Hao , Tao Jia , Xinyue Zhang , Songmei Geng
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Abstract

Background

Topical tacrolimus, although widely used in the treatment of dermatoses, presents with an immediate irritation on initial application resembling a pseudo-allergic reaction. Mas-related G protein-coupled receptor X2 (MRGPRX2) in mast cells (MCs) mediates drug-induced pseudo-allergic reaction and immunoglobulin E (IgE)-independent pruritis in chronic skin diseases. However, the immunosuppression mechanism of tacrolimus on MCs via MRGPRX2 has not been reported.

Objective

To investigate the role of MRGPRX2 and the mechanism of action of tacrolimus on its short-term and long-term applications.

Methods

Wild-type mice, KitW-sh/W-sh mice, and MrgprB2-deficient (MUT) mice were used to study the effect of tacrolimus on in vivo anaphylaxis model. LAD2 cells and MRGPRX2-knockdown LAD2 cells were specifically used to derive the associated mechanism of the tacrolimus effect.

Results

Short-term application of tacrolimus triggers IgE-independent activation of MCs via MRGPRX2/B2 in both in vivo and in vitro experiments. Tacrolimus binds to MRGPRX2, which was verified by fluorescently labeled tacrolimus in cells. On long-term treatment with tacrolimus, the initial allergic reaction fades away corresponding with the downregulation of MRGPRX2, which leads to decreased release of inflammatory cytokines (P < 0.05 to P < 0.001).

Conclusion

Short-term treatment with tacrolimus induces pseudo-allergic reaction via MRGPRX2/B2 in MCs, whereas long-term treatment downregulates expression of MRGPRX2/B2, which may contribute to its potent immunosuppressive effect in the treatment of various skin diseases.

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他克莫司通过肥大细胞相关G蛋白偶联受体X2对肥大细胞介导的过敏和炎症的双重作用。
背景:局部他克莫司虽然广泛用于治疗皮肤病,但在初次应用时表现出立即刺激,类似于伪过敏反应。肥大细胞(MCs)中mass相关G蛋白偶联受体X2 (MRGPRX2)介导慢性皮肤病中药物诱导的假性过敏反应和免疫球蛋白E (IgE)非依赖性瘙痒。然而,他克莫司通过MRGPRX2对MCs的免疫抑制机制尚未见报道。目的:探讨MRGPRX2的作用及他克莫司对其短期和长期应用的作用机制。方法:采用野生型小鼠、KitW-sh/W-sh小鼠和mrgprb2缺陷(MUT)小鼠,研究他克莫司对体内过敏反应模型的影响。LAD2细胞和mrgprx2敲低的LAD2细胞被专门用来推导他克莫司效应的相关机制。结果:在体内和体外实验中,短期应用他克莫司可通过MRGPRX2/B2触发MCs的ige非依赖性激活。他克莫司与MRGPRX2结合,通过荧光标记他克莫司在细胞中进行验证。长期服用他克莫司,初始过敏反应逐渐消失,MRGPRX2下调,导致炎症细胞因子释放减少(P)结论:短期服用他克莫司可通过MRGPRX2/B2诱导MCs假过敏反应,而长期服用他克莫司可下调MRGPRX2/B2的表达,这可能是其治疗多种皮肤病的有效免疫抑制作用的原因之一。
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