IL-33-PIN1-IRAK-M 轴对于 IL-33 诱导的过敏性气道炎症中的 2 型免疫至关重要。
The IL-33-PIN1-IRAK-M axis is critical for type 2 immunity in IL-33-induced allergic airway inflammation.
机构信息
Division of Translational Therapeutics, Department of Medicine and Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
Department of Molecular Biology & Genetics, Cornell University, Ithaca, NY, 14853, USA.
出版信息
Nat Commun. 2018 Apr 23;9(1):1603. doi: 10.1038/s41467-018-03886-6.
Interleukin 33 (IL-33) is among the earliest-released cytokines in response to allergens that orchestrate type 2 immunity. The prolyl cis-trans isomerase PIN1 is known to induce cytokines for eosinophil survival and activation by stabilizing cytokines mRNAs, but the function of PIN1 in upstream signaling pathways in asthma is unknown. Here we show that interleukin receptor associated kinase M (IRAK-M) is a PIN1 target critical for IL-33 signaling in allergic asthma. NMR analysis and docking simulations suggest that PIN1 might regulate IRAK-M conformation and function in IL-33 signaling. Upon IL-33-induced airway inflammation, PIN1 is activated for binding with and isomerization of IRAK-M, resulting in IRAK-M nuclear translocation and induction of selected proinflammatory genes in dendritic cells. Thus, the IL-33-PIN1-IRAK-M is an axis critical for dendritic cell activation, type 2 immunity and IL-33 induced airway inflammation.
白细胞介素 33（IL-33）是最早响应过敏原的细胞因子之一，可调控 2 型免疫。脯氨酰顺反异构酶 PIN1 已知通过稳定细胞因子 mRNA 来诱导嗜酸性粒细胞存活和激活的细胞因子，但 PIN1 在哮喘中上游信号通路中的功能尚不清楚。在这里，我们发现白细胞介素受体相关激酶 M（IRAK-M）是 IL-33 信号转导中 PIN1 的一个关键靶点，在过敏性哮喘中起作用。NMR 分析和对接模拟表明，PIN1 可能调节 IRAK-M 在 IL-33 信号转导中的构象和功能。在 IL-33 诱导的气道炎症中，PIN1 被激活以与 IRAK-M 结合并发生异构化，导致 IRAK-M 核易位，并在树突状细胞中诱导选定的促炎基因。因此，IL-33-PIN1-IRAK-M 是树突状细胞激活、2 型免疫和 IL-33 诱导的气道炎症的关键轴。
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