The p110δ subunit of PI3K regulates bone marrow-derived eosinophil trafficking and airway eosinophilia in allergen-challenged mice
The p110δ subunit of PI3K regulates bone marrow-derived eosinophil trafficking and airway eosinophilia in allergen-challenged mice
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DOI：
10.1152/ajplung.00005.2012
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发表时间：
2012-06-01
影响因子：
4.9
通讯作者：
Sriramarao, P.
中科院分区：
文献类型：
--
作者：
Kang, Bit Na;Ha, Sung Gil;Sriramarao, P.
Kang BN，Ha SG，Ge XN，Hosseinkhani MR，Bahaie NS，Greenberg Y，布卢门塔尔MN，Puri KD，Rao SP，Sriramarao P. The p110 delta subunit of PI3 K regulates bone marrow-derived eosinophil trafficking and airway eosinophilia in allergen-charged mice.美国生理学杂志肺细胞分子生理学302：L1179-L1191，2012年。首次发表于2012年3月16日; doi：10.1152/ajplung.00005.2012.-嗜酸性粒细胞在过敏性气道炎症中的运输和募集是由磷脂酰肌醇3-激酶（PI 3 K）家族的信号分子介导的。使用选择性药理学抑制剂（IC 87114）研究了PI 3 K p110 δ亚基（PI 3 K p110 δ）在调节嗜酸性粒细胞运输和募集中所起的作用。用PI 3 K p110 δ抑制剂治疗显著降低了小鼠骨髓来源的嗜酸性粒细胞（BM-Eos）与VCAM-1以及ICAM-1的粘附，并抑制了与Mac-1表达降低和Mac-1和α 4的异常细胞表面定位/分布相关的活化诱导的细胞形态变化。输注的BM-Eos表现出与媒介物处理的小鼠相比，在用IC 87114处理的小鼠的发炎的提睾肌微血管中显著降低的滚动和粘附。此外，抑制PI 3 K p110 δ显著减弱了eotaxin-1诱导的BM-Eos迁移，并阻止了eotaxin-1诱导的细胞骨架和细胞形态的变化。在BM-Eos中用siRNA敲低PI 3 K p110 delta导致滚动、粘附和迁移减少，以及抑制激活诱导的细胞形态变化，验证其在调节运输和迁移中的作用。最后，在蟑螂抗原诱导的过敏性气道炎症的小鼠模型中，口服PI 3 K p110 δ抑制剂显著抑制气道嗜酸性粒细胞的募集，导致对乙酰甲胆碱的气道高反应性减弱，粘液分泌减少，促炎分子（在炎症区-1和intelectin-1中发现）的表达减少。总之，这些发现表明PI 3 K p110 delta通过调节粘附分子的表达和定位/分布以及促进细胞形态的变化，在炎症期间有利于募集，从而在介导BM-Eos运输和迁移中发挥重要作用。
Kang BN, Ha SG, Ge XN, Hosseinkhani MR, Bahaie NS, Greenberg Y, Blumenthal MN, Puri KD, Rao SP, Sriramarao P. The p110 delta subunit of PI3K regulates bone marrow-derived eosinophil trafficking and airway eosinophilia in allergen-challenged mice. Am J Physiol Lung Cell Mol Physiol 302: L1179-L1191, 2012. First published March 16, 2012; doi: 10.1152/ajplung.00005.2012.-Trafficking and recruitment of eosinophils during allergic airway inflammation is mediated by the phosphatidylinositol 3-kinase (PI3K) family of signaling molecules. The role played by the p110 delta subunit of PI3K (PI3K p110 delta) in regulating eosinophil trafficking and recruitment was investigated using a selective pharmacological inhibitor (IC87114). Treatment with the PI3K p110 delta inhibitor significantly reduced murine bone marrow-derived eosinophil (BM-Eos) adhesion to VCAM-1 as well as ICAM-1 and inhibited activation-induced changes in cell morphology associated with reduced Mac-1 expression and aberrant cell surface localization/distribution of Mac-1 and alpha 4. Infused BM-Eos demonstrated significantly decreased rolling and adhesion in inflamed cremaster muscle microvessels of mice treated with IC87114 compared with vehicle-treated mice. Furthermore, inhibition of PI3K p110 delta significantly attenuated eotaxin-1-induced BM-Eos migration and prevented eotaxin-1-induced changes in the cytoskeleton and cell morphology. Knockdown of PI3K p110 delta with siRNA in BM-Eos resulted in reduced rolling, adhesion, and migration, as well as inhibition of activation-induced changes in cell morphology, validating its role in regulating trafficking and migration. Finally, in a mouse model of cockroach antigen-induced allergic airway inflammation, oral administration of the PI3K p110 delta inhibitor significantly inhibited airway eosinophil recruitment, resulting in attenuation of airway hyperresponsiveness in response to methacholine, reduced mucus secretion, and expression of proinflammatory molecules (found in inflammatory zone-1 and intelectin-1). Overall, these findings indicate the important role played by PI3K p110 delta in mediating BM-Eos trafficking and migration by regulating adhesion molecule expression and localization/distribution as well as promoting changes in cell morphology that favor recruitment during inflammation.