Phosphoinositide 3-Kinase δ Regulates Dectin-2 Signaling and the Generation of Th2 and Th17 Immunity.
Phosphoinositide 3-Kinase δ Regulates Dectin-2 Signaling and the Generation of Th2 and Th17 Immunity.
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磷酸肌醇3-激酶δ调节Dectin-2信号传导以及Th2和Th17免疫的产生。
DOI：
10.4049/jimmunol.1502485
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发表时间：
2016-07-01
期刊：
影响因子：
--
通讯作者：
Barrett NA
中科院分区：
文献类型：
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作者：
Lee MJ;Yoshimoto E;Saijo S;Iwakura Y;Lin X;Katz HR;Kanaoka Y;Barrett NA
C型凝集素受体（Dectin）Dectin-2可触发白三烯C4合酶（LTC 4S）依赖性的半胱氨酰白三烯（cys-LTs）生成以及CARD 9和NF-κ B依赖性的细胞因子（如IL-23、IL-6和TNF-α）生成，从而分别促进Th 2和Th 17免疫。Dectin-2激活也激发2型细胞因子IL-33，但Dectin-2诱导这些不同的先天介质的机制知之甚少。在这里，我们确定了一个共同的上游要求磷脂酰肌醇3-激酶δ（PI 3 K δ）的活性产生的每一个Dectin-2依赖性介导的屋尘螨物种，粉尘螨（Dermatophagoides farinae）（Df），使用药理学抑制和siRNA敲低骨髓来源的树突状细胞（BMDC）中的PI 3 K δ。PI 3 K δ的活性依赖于脾酪氨酸激酶（Syk），并调节蛋白激酶Cδ的活性，表明PI 3 K δ是一个近端Syk依赖的信号中间体。PI 3 K δ的抑制也减少了由Dectin-2交联引起的cys-LT和细胞因子，证实了该分子在Dectin-2信号传导中的重要性。使用过继转移模型，我们证明了PI 3 K δ的抑制深刻地降低了BMDC对受体小鼠响应于Df的Th 2和Th 17肺部炎症的敏感性的能力。此外，在WT小鼠致敏期间施用PI 3 K δ抑制剂防止了Df诱导的肺部炎症的产生。这些结果表明，PI 3 K δ调节Dectin-2信号传导及其DC功能。
The C-type lectin receptor (CLR) Dectin-2 can trigger the leukotriene C4 synthase (LTC4S)-dependent generation of cysteinyl leukotrienes (cys-LTs) and the CARD9- and NF-κB-dependent generation of cytokines, such as IL-23, IL-6, and TNF-α, to promote Th2 and Th17 immunity, respectively. Dectin-2 activation also elicits the type 2 cytokine IL-33, but the mechanism by which Dectin-2 induces these diverse innate mediators is poorly understood. Here we identify a common upstream requirement for phosphoinositide 3-kinase delta (PI3Kδ) activity for the generation of each Dectin-2-dependent mediator elicited by the house dust mite species, Dermatophagoides farinae (Df), using both pharmacologic inhibition and siRNA knockdown of PI3Kδ in bone marrow-derived dendritic cells (BMDCs). PI3Kδ activity depends on Spleen tyrosine kinase (Syk) and regulates the activity of protein kinase Cδ, indicating that PI3Kδ is a proximal Syk-dependent signaling intermediate. Inhibition of PI3Kδ also reduces cys-LTs and cytokines elicited by Dectin-2 cross-linking, confirming the importance of this molecule in Dectin-2 signaling. Using an adoptive transfer model, we demonstrate that inhibition of PI3Kδ profoundly reduces the capacity of BMDCs to sensitize recipient mice for Th2 and Th17 pulmonary inflammation in response to Df. Furthermore, administration of a PI3Kδ inhibitor during the sensitization of WT mice prevents the generation of Df-induced pulmonary inflammation. These results demonstrate that PI3Kδ regulates Dectin-2 signaling and its DC function.