Neuronal Wiskott-Aldrich syndrome protein regulates Pseudomonas aeruginosa-induced lung vascular permeability through the modulation of actin cytoskeletal dynamics.
Neuronal Wiskott-Aldrich syndrome protein regulates Pseudomonas aeruginosa-induced lung vascular permeability through the modulation of actin cytoskeletal dynamics.
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DOI：
10.1096/fj.201902915r
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发表时间：
2020-02
期刊：
影响因子：
--
通讯作者：
Ding Q
中科院分区：
文献类型：
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作者：
Che P;Wagener BM;Zhao X;Brandon AP;Evans CA;Cai GQ;Zhao R;Xu ZX;Han X;Pittet JF;Ding Q
肺水肿与血管通透性增加是假单胞菌（P.）致急性肺损伤铜绿假单胞菌诱导的血管通透性的机制还不清楚。在本研究中，我们研究了神经元Wiskott-Aldrich综合征蛋白（N-WASP）在调节铜绿假单胞菌诱导的血管通透性中的作用。使用肺微血管内皮细胞和肺泡上皮细胞，我们证明，N-WASP下调衰减铜绿假单胞菌诱导的肌动蛋白应力纤维的形成，并防止细胞旁通透性。铜绿假单胞菌诱导VE-钙粘蛋白和β-连环蛋白之间的解离，但增加N-WASP和VE-钙粘蛋白之间的结合，表明N-WASP在促进铜绿假单胞菌诱导的粘附连接破裂中的作用。铜绿假单胞菌增加N-WASP-Y256磷酸化，这需要Rho GT3和黏着斑激酶的激活。N-WASP-Y256磷酸化的增加促进N-WASP和整联蛋白αVβ6的结合以及TGF-β介导的跨肺泡上皮细胞的渗透性。通过N-WASP-Y256 F过表达抑制N-WASP-Y256磷酸化阻断了N-WASP在铜绿假单胞菌诱导的肌动蛋白应力纤维形成中的作用，并增加了细胞旁通透性。在体内，N-WASP敲低减弱了铜绿假单胞菌肺炎小鼠模型中肺水肿的发展并改善了存活率。总之，我们的数据表明，N-WASP通过调节肌动蛋白细胞骨架动力学在铜绿假单胞菌诱导的血管通透性和肺水肿中起着至关重要的作用。
Pulmonary edema associated with increased vascular permeability is a severe complication of Pseudomonas (P.) aeruginosa-induced acute lung injury. The mechanisms underlying P aeruginosa-induced vascular permeability are not well understood. In the present study, we investigated the role of neuronal Wiskott Aldrich syndrome protein (N-WASP) in modulating P aeruginosa-induced vascular permeability. Using lung microvascular endothelial and alveolar epithelial cells, we demonstrated that N-WASP downregulation attenuated P aeruginosa-induced actin stress fiber formation and prevented paracellular permeability. P aeruginosa-induced dissociation between VE-cadherin and β-catenin, but increased association between N-WASP and VE-cadherin, suggesting a role for N-WASP in promoting P aeruginosa-induced adherens junction rupture. P aeruginosa increased N-WASP-Y256 phosphorylation, which required the activation of Rho GTPase and focal adhesion kinase. Increased N-WASP-Y256 phosphorylation promotes N-WASP and integrin αVβ6 association as well as TGF-β-mediated permeability across alveolar epithelial cells. Inhibition of N-WASP-Y256 phosphorylation by N-WASP-Y256F overexpression blocked N-WASP effects in P aeruginosa-induced actin stress fiber formation and increased paracellular permeability. In vivo, N-WASP knockdown attenuated the development of pulmonary edema and improved survival in a mouse model of P aeruginosa pneumonia. Together, our data demonstrate that N-WASP plays an essential role in P aeruginosa-induced vascular permeability and pulmonary edema through the modulation of actin cytoskeleton dynamics.