Regulation of PTEN activity by p38δ-PKD1 signaling in neutrophils confers inflammatory responses in the lung.
Regulation of PTEN activity by p38δ-PKD1 signaling in neutrophils confers inflammatory responses in the lung.
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DOI：
10.1084/jem.20120677
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发表时间：
2012-11-19
期刊：
影响因子：
--
通讯作者：
Ricci R
中科院分区：
文献类型：
--
作者：
Ittner A;Block H;Reichel CA;Varjosalo M;Gehart H;Sumara G;Gstaiger M;Krombach F;Zarbock A;Ricci R
p38 MAP激酶p38 d的缺失导致肺泡中性粒细胞积聚减少，并通过激活蛋白激酶D1和PTEN减轻急性肺损伤。尽管中性粒细胞在解决炎性损伤中发挥作用，但其触发炎症诱导的急性肺损伤（ALI），最终导致急性呼吸窘迫综合征（ARDS），这是人类中具有高死亡率的常见并发症。中性粒细胞募集到炎症部位的分子机制仍然知之甚少。在这里，我们发现p38 MAP激酶p38δ是中性粒细胞募集到炎症部位所必需的。小鼠中p38δ的整体和骨髓限制性缺失导致肺泡中性粒细胞积聚减少和ALI减轻。p38δ在中性粒细胞中抵消其下游靶蛋白激酶D1（PKD 1）的活性，并且PKD 1的骨髓限制性失活导致肺部炎症加重。重要的是，p38δ和PKD 1反过来调节中性粒细胞中的PTEN活性，从而控制它们的外渗和趋化性。PKD 1磷酸化p85α以增强其与PTEN的相互作用，导致极化的PTEN活性，从而调节中性粒细胞迁移。因此，中性粒细胞中异常的p38δ-PKD 1信号传导可能是人类ALI和危及生命的ARDS发展的基础。
Deletion of p38 MAP kinase p38 d results in decreased alveolar neutrophil accumulation and attenuation of acute lung injury through activation of protein kinase D1 and PTEN. Despite their role in resolving inflammatory insults, neutrophils trigger inflammation-induced acute lung injury (ALI), culminating in acute respiratory distress syndrome (ARDS), a frequent complication with high mortality in humans. Molecular mechanisms underlying recruitment of neutrophils to sites of inflammation remain poorly understood. Here, we show that p38 MAP kinase p38δ is required for recruitment of neutrophils into inflammatory sites. Global and myeloid-restricted deletion of p38δ in mice results in decreased alveolar neutrophil accumulation and attenuation of ALI. p38δ counteracts the activity of its downstream target protein kinase D1 (PKD1) in neutrophils and myeloid-restricted inactivation of PKD1 leads to exacerbated lung inflammation. Importantly, p38δ and PKD1 conversely regulate PTEN activity in neutrophils, thereby controlling their extravasation and chemotaxis. PKD1 phosphorylates p85α to enhance its interaction with PTEN, leading to polarized PTEN activity, thereby regulating neutrophil migration. Thus, aberrant p38δ–PKD1 signaling in neutrophils may underlie development of ALI and life-threatening ARDS in humans.
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影响因子：
21.3
作者：
Eiseler T;Döppler H;Yan IK;Kitatani K;Mizuno K;Storz P
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DOI：
10.1073/pnas.0908899107
发表时间：
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