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MiRNA-155 controls mast cell activation by regulating the PI3Kγ pathway and anaphylaxis in a mouse model

机译:MiRNA-155通过调节小鼠模型中的PI3Kγ途径和过敏反应来控制肥大细胞活化

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Background Mast cells (MCs) play a central role in allergic and inflammatory disorders by rapid degranulation and release of inflammatory mediators upon antigen-driven engagement of the FcεRI. Receptor-mediated MC responses are controlled by the activation of different isoforms of phosphoinositide-3-kinase (PI3K) and the downstream signaling processes. Recent evidence suggests that miRNAs are important molecular players regulating the PI3K/Akt pathway. Methods The role of miR-155 in the regulation of MC functions in vivo was studied in the passive cutaneous anaphylaxis (PCA) MC-dependent model. WT and miR-155-/- mice were injected intradermally with anti-DNP-IgE and intravenously with the antigen DNP-HSA. Ear swelling was assessed to evaluate the anaphylactic response. All investigations, to characterize miR-155 specific activities in MCs, were conducted comparing WT and miR-155-/- bone marrow-derived MCs (BMMCs). Results We report that miR-155-/- mice display enhanced anaphylaxis reactions. Although miR-155-/- BMMCs show normal development, proliferation, and survival, miR-155 deficiency enhances FcεRI-mediated degranulation and release of TNF-α, IL-13, and IL-6. Interestingly, the level of Akt phosphorylation on both of its regulatory residues Thr308 and Ser473 was increased in miR-155-/- compared to WT BMMCs. Gene expression profiling showed that miR-155-/- BMMCs exhibited significantly increased expression of the adapter PI3Kγ subunits Pik3r5 (p101) and Pik3r6 (p84, p87PIKAP). Furthermore, selective blockade of the PI3Kγ pathway inhibited degranulation in miR-155-/- BMMCs. Conclusions Thus, we suggest that miR-155 plays a critical role in FcεRI-mediated MC responses by modulating components of the PI3Kγ pathway. This newly identified mechanism of miRNA-controlled MC activation may affect the initiation and maintenance of allergic disorders.
机译:背景肥大细胞(MCs)在抗原驱动的FcεRI结合后迅速脱粒并释放炎性介质,从而在变应性和炎性疾病中发挥重要作用。受体介导的MC反应受磷酸肌醇3-激酶(PI3K)的不同同工型的激活和下游信号传导过程的控制。最近的证据表明,miRNA是调节PI3K / Akt途径的重要分子。方法在被动皮肤过敏(PCA)MC依赖性模型中研究了miR-155在体内MC功能调节中的作用。给WT和miR-155-/-小鼠皮内注射抗DNP-IgE,并静脉内注射抗原DNP-HSA。评估耳朵肿胀以评估过敏反应。进行了所有研究,以表征miR-155在MC中的特定活性,比较了WT和miR-155-/-骨髓源性MC(BMMC)。结果我们报告miR-155-/-小鼠显示出增强的过敏反应。尽管miR-155-/-BMMC显示正常发育,增殖和存活,但miR-155缺乏会增强FcεRI介导的脱粒和TNF-α,IL-13和IL-6的释放。有趣的是,与野生型BMMC相比,miR-155-/-的调节残基Thr308和Ser473的Akt磷酸化水平均增加。基因表达谱分析表明,miR-155-/-BMMC表现出衔接子PI3Kγ亚基Pik3r5(p101)和Pik3r6(p84,p87PIKAP)的表达显着增加。此外,PI3Kγ途径的选择性阻断抑制了miR-155-/-BMMC中的脱粒。结论因此,我们建议miR-155在FcεRI介导的MC反应中起关键作用,其通过调节PI3Kγ途径的成分。新确定的miRNA控制的MC激活机制可能影响过敏性疾病的发生和维持。

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