Research Center Borstel, Borstel, Germany.
Allergy. 2014 Jun;69(6):752-62. doi: 10.1111/all.12407. Epub 2014 Apr 15.
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.
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).
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, p87(PIKAP) ). Furthermore, selective blockade of the PI3Kγ pathway inhibited degranulation in miR-155(-/-) BMMCs.
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.
肥大细胞（MCs）通过快速脱颗粒和释放炎症介质，在抗原驱动 FcεRI 结合后，在过敏和炎症性疾病中发挥核心作用。受体介导的 MC 反应受不同同工型的磷酸肌醇 3-激酶（PI3K）的激活和下游信号转导过程控制。最近的证据表明，miRNA 是调节 PI3K/Akt 通路的重要分子调控因子。
在被动皮肤过敏（PCA）MC 依赖性模型中研究了 miR-155 在调节 MC 功能中的作用。用抗 DNP-IgE 皮内注射 WT 和 miR-155(-/-) 小鼠，并静脉注射抗原 DNP-HSA。评估耳朵肿胀以评估过敏反应。为了研究 miR-155 在 MC 中的特异性作用，所有的研究都在 WT 和 miR-155(-/-) 骨髓衍生 MC（BMMC）中进行。
我们报告说，miR-155(-/-) 小鼠表现出增强的过敏反应。尽管 miR-155(-/-) BMMC 显示出正常的发育、增殖和存活，但 miR-155 缺乏增强了 FcεRI 介导的脱颗粒和 TNF-α、IL-13 和 IL-6 的释放。有趣的是，与 WT BMMC 相比，miR-155(-/-) BMMC 中 Akt 的两个调节残基 Thr308 和 Ser473 的磷酸化水平增加。基因表达谱分析显示，miR-155(-/-) BMMC 表现出 PI3Kγ 亚基 Pik3r5(p101) 和 Pik3r6(p84、p87(PIKAP))的表达显著增加。此外，PI3Kγ 途径的选择性阻断抑制了 miR-155(-/-) BMMC 的脱颗粒作用。
因此，我们认为 miR-155 通过调节 PI3Kγ 途径的组成部分在 FcεRI 介导的 MC 反应中发挥关键作用。这种新发现的 miRNA 控制 MC 激活的机制可能会影响过敏疾病的起始和维持。
