Crucial role of SLP-76 and ADAP for neutrophil recruitment in mouse kidney ischemia-reperfusion injury.
Crucial role of SLP-76 and ADAP for neutrophil recruitment in mouse kidney ischemia-reperfusion injury.
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DOI：
10.1084/jem.20111493
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发表时间：
2012-02-13
期刊：
影响因子：
--
通讯作者：
Zarbock A
中科院分区：
文献类型：
--
作者：
Block H;Herter JM;Rossaint J;Stadtmann A;Kliche S;Lowell CA;Zarbock A
急性损伤期间白细胞向肾脏的募集是由 E-选择素介导的滚动介导的，并且需要 SLP-76 和接头蛋白 ADAP。中性粒细胞会引发炎症引起的急性肾损伤（AKI），这是人类常见且可能致命的情况。中性粒细胞募集到炎症部位的分子机制已被证明难以捉摸。在本研究中，我们证明 SLP-76（含有 76 kD 的 SH2 结构域的白细胞磷蛋白）和 ADAP（促进粘附和脱颗粒的衔接蛋白）参与 E-选择素介导的整合素激活和缓慢的白细胞滚动，从而促进小鼠缺血再灌注诱导的 AKI。通过使用基因工程小鼠和转导的 Slp76−/− 原代白细胞，我们证明 ADAP 以及两个位于 N 末端的酪氨酸和 SLP-76 的 SH2 结构域是下游信号传导和缓慢白细胞滚动所必需的。 Tec 家族激酶 Bruton 酪氨酸激酶是 SLP-76 的下游，与 ADAP 一起调节 PI3Kγ（磷酸肌醇 3-激酶 -γ）和 PLCγ2（磷脂酶 Cγ2）依赖性途径。阻断这两条途径可以完全消除整合素亲和力和亲和力调节。因此，SLP-76 和 ADAP 参与 E-选择素介导的整合素激活和中性粒细胞向发炎肾脏的募集，这可能是人类发生危及生命的缺血再灌注诱发的 AKI 的基础。
Leukocyte recruitment to the kidney during acute injury is mediated by E-selectin–mediated rolling and requires SLP-76 and the adaptor protein ADAP. Neutrophils trigger inflammation-induced acute kidney injury (AKI), a frequent and potentially lethal occurrence in humans. Molecular mechanisms underlying neutrophil recruitment to sites of inflammation have proved elusive. In this study, we demonstrate that SLP-76 (SH2 domain–containing leukocyte phosphoprotein of 76 kD) and ADAP (adhesion and degranulation promoting adaptor protein) are involved in E-selectin–mediated integrin activation and slow leukocyte rolling, which promotes ischemia-reperfusion–induced AKI in mice. By using genetically engineered mice and transduced Slp76−/− primary leukocytes, we demonstrate that ADAP as well as two N-terminal–located tyrosines and the SH2 domain of SLP-76 are required for downstream signaling and slow leukocyte rolling. The Tec family kinase Bruton tyrosine kinase is downstream of SLP-76 and, together with ADAP, regulates PI3Kγ (phosphoinositide 3-kinase–γ)- and PLCγ2 (phospholipase Cγ2)-dependent pathways. Blocking both pathways completely abolishes integrin affinity and avidity regulation. Thus, SLP-76 and ADAP are involved in E-selectin–mediated integrin activation and neutrophil recruitment to inflamed kidneys, which may underlie the development of life-threatening ischemia-reperfusion–induced AKI in humans.
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影响因子：
5.6
作者：
Heuer, K;Arbuzova, A;Freund, C
通讯作者：
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影响因子：
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DOI：
10.1073/pnas.94.14.7493
发表时间：
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影响因子：
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