The role of endothelial PI3K-γ activity in neutrophil trafficking
The role of endothelial PI3K-γ activity in neutrophil trafficking
复制标题
DOI：
10.1182/blood-2005-01-0023
复制
发表时间：
2005-07-01
期刊：
影响因子：
20.3
通讯作者：
Diacovo, TG
中科院分区：
文献类型：
--
作者：
Puri, KD;Doggett, TA;Diacovo, TG
中性粒细胞中的磷酸肌醇3-激酶γ（PI 3 K γ）在这些细胞定向迁移到炎症组织中起关键作用。在这项研究中，我们证明了PI 3 K γ活性的内皮成分相对于其白细胞对应物在支持中性粒细胞与发炎血管壁的相互作用中的重要性。尽管p110 γ（-/-）小鼠的中性粒细胞中Ib类PI 3 K功能重建，但我们观察到这些细胞在急性肺损伤模型中的积累减少了45%。从机制上讲，这似乎是由于选择素介导的粘附的扰动，表现为对肿瘤坏死因子α（TNF α）的反应，体内野生型（WT）中性粒细胞附着于p1101 γ（-/-）微血管的减少70%，滚动速度增加17倍。这种粘附的改变进一步增强了p110 δ的缺陷，这表明这两个催化亚基的活性是必需的有效捕获中性粒细胞的精氨酸刺激的内皮细胞。有趣的是，p110 γ（-/-）小鼠中E-选择素介导的粘附受损超过95%，但未观察到核因子κ B（NF-κ B）诱导的基因表达缺陷。这些发现表明，在白细胞和内皮细胞中表达的I类PI 3 Ks之间存在先前未被认识的伙伴关系，其组合是免疫活性细胞有效运输至炎症部位所需的。(c)2005年，美国血液学会。
Phosphoinositide 3-kinase gamma (PI3K gamma) in neutrophils plays a critical role in the directed migration of these cells into inflamed tissues. In this study, we demonstrate the importance of the endothelial component of PI3K gamma activity relative to its leukocyte counterpart in supporting neutrophil interactions with the inflamed vessel wall. Despite the reconstitution of class-Ib PI3K function in neutrophils of p110 gamma(-/-) mice, we observed a 45% reduction in accumulation of these cells in an acute lung injury model. Mechanistically, this appears to result from a perturbation in selectin-mediated adhesion as manifested by a 70% reduction in wild-type (WT) neutrophil attachment to and 17-fold increase in rolling velocities on p1101 gamma(-/-) microvessels in vivo in response to tumor necrosis factor alpha (TNF alpha). This alteration in adhesion was further augmented by a deficiency in p110 delta, suggesting that the activity of both catalytic subunits is required for efficient capture of neutrophils by cytokine-stimulated endothelium. Interestingly, E-selectin-mediated adhesion in p110 gamma(-/-) mice was impaired by more than 95%, but no defect in nuclear factor kappa B (NF-kappa B)-induced gene expression was observed. These findings suggest a previously unrecognized partnership between class-I PI3Ks expressed in leukocytes and endothellum, the combination of which is required for the efficient trafficking of immunocompetent cells to sites of inflammation. (c) 2005 by The American Society of Hematology.