Raf kinase inhibitor protein negatively regulates FcεRI-mediated mast cell activation and allergic response
Raf kinase inhibitor protein negatively regulates FcεRI-mediated mast cell activation and allergic response
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Raf 激酶抑制剂蛋白负向调节 FcγRI 介导的肥大细胞活化和过敏反应。
DOI：
10.1073/pnas.1805474115
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发表时间：
2018-10-16
影响因子：
11.1
通讯作者：
Wang, Xiaojian
中科院分区：
文献类型：
--
作者：
Lin, Wenlong;Su, Fasheng;Wang, Xiaojian
意义肥大细胞激活导致多种过敏性疾病，如哮喘、鼻炎和特应性皮炎。在这里，我们证明了Raf激酶抑制蛋白(RKIP)作为肥大细胞激活的抑制因子。在体内，RKIP对肥大细胞介导的过敏反应和过敏性哮喘的发病机制具有负性调节作用。此外，哮喘患者外周血中RKIP的表达显著下调。总之，我们的发现不仅表明RKIP在控制肥大细胞介导的过敏反应中发挥着重要作用，而且还为肥大细胞相关过敏性疾病的治疗靶点提供了洞察力。免疫球蛋白E与肥大细胞上高亲和力受体(FcεRI)的交叉连接所触发的信号级联可导致多种变态反应性疾病，如哮喘、鼻炎和特应性皮炎。抑制肥大细胞激活的细胞内信号对于恢复内环境平衡至关重要。在本研究中，我们发现Raf激酶抑制蛋白(RKIP)负向调节肥大细胞的激活。RKIP缺陷的肥大细胞表现出比野生型肥大细胞更强的Ig E−FcεRI介导的激活。肥大细胞中的RKIP缺陷使小鼠对Ig E−FcεRI介导的过敏反应和卵清蛋白诱导的呼吸道炎症更加敏感。在机制上，RKIP与PI3K的P85亚基相互作用，阻止其与Grb2相关的结合蛋白2(Gb2)结合，最终抑制PI3K/Akt/NF-κB复合体的激活及其下游信号转导。此外，哮喘患者外周血和Ig E−FcεRI刺激的肥大细胞中RKIP的表达显著下调。总之，我们的发现不仅表明RKIP在控制肥大细胞介导的过敏反应中发挥着重要作用，而且还为肥大细胞相关过敏性疾病的治疗靶点提供了洞察力。
Significance Mast cell activation contributes to multiple allergic disorders, such as asthma, rhinitis, and atopic dermatitis. Here, we demonstrate that the Raf kinase inhibitor protein (RKIP) functions as an inhibitor of mast cell activation. RKIP negatively regulates the pathogeneses of the mast cell-mediated anaphylactic response and allergic asthma in vivo. Furthermore, the expression of RKIP was significantly down-regulated in peripheral blood from asthma patients. Collectively, our findings not only suggest that RKIP plays an important role in controlling mast cell-mediated allergic responses but also provide insight into therapeutic targets for mast cell-related allergic diseases. The signaling cascades triggered by the cross-linkage of immunoglobulin E (IgE) with its high-affinity receptor (FcεRI) on mast cells contribute to multiple allergic disorders, such as asthma, rhinitis, and atopic dermatitis. Restraint of intracellular signals for mast cell activation is essential to restore homeostasis. In this study, we found that Raf kinase inhibitor protein (RKIP) negatively regulated mast cell activation. RKIP-deficient mast cells showed greater IgE−FcεRI-mediated activation than wild-type mast cells. Consistently, RKIP deficiency in mast cells rendered mice more sensitive to IgE−FcεRI-mediated allergic responses and ovalbumin-induced airway inflammation. Mechanistically, RKIP interacts with the p85 subunit of PI3K, prevents it from binding to GRB2-associated binding protein 2 (Gab2), and eventually inhibits the activation of the PI3K/Akt/NF-κB complex and its downstream signaling. Furthermore, the expression of RKIP was significantly down-regulated in the peripheral blood of asthma patients and in the IgE−FcεRI-stimulated mast cells. Collectively, our findings not only suggest that RKIP plays an important role in controlling mast cell-mediated allergic responses but also provide insight into therapeutic targets for mast cell-related allergic diseases.