Growth Arrest Specific-6 and Axl Coordinate Inflammation and Hypertension.
Growth Arrest Specific-6 and Axl Coordinate Inflammation and Hypertension.
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生长抑制特异性-6和Axl协调炎症和高血压。
DOI：
10.1161/circresaha.121.319643
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发表时间：
2021-11-12
影响因子：
20.1
通讯作者：
Harrison, David G.
中科院分区：
文献类型：
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作者：
Van Beusecum, Justin P.;Barbaro, Natalia R.;Smart, Charles D.;Patrick, David M.;Loperena, Roxana;Zhao, Shilin;de la Visitacion, Nestor;Ao, Mingfang;Xiao, Liang;Shibao, Cyndya A.;Harrison, David G.
内皮细胞与单核细胞关系密切，活化的内皮细胞可促进单核细胞向巨噬细胞和树突状细胞转化。最近，已经描述了表达受体酪氨酸激酶Axl和凝集素Siglec-6的人DC的子集，并将其称为AS DC。我们试图确定人类高血压中循环AS DC是否增加，并检查Axl信号传导如何促成这种疾病。我们证明，高血压患者的循环AS DC比正常血压对照组增加。人的脉压也与Axl激动剂生长停滞特异性6（GAS 6）的血浆水平相关。将人内皮细胞暴露于10%周期性拉伸增加了GAS 6的释放，促进了Axl信号传导并引起AS DC形成;通过用R428阻断Axl或通过siRNA敲低内皮GAS 6或Axl来抑制这些事件。人单核细胞中的GAS 6/Axl信号通过NLRP 3/半胱天冬酶-1增强白细胞介素1-β的产生，并引起免疫原性isoLG-蛋白加合物的积累。在小鼠中，Axl抑制剂R428或Axl的整体缺失减轻了由血管紧张素II（Ang II）输注引起的高血压和肾脏炎症。骨髓移植研究表明，基质和免疫Axl在血管紧张素II诱导的高血压中的作用。最后，在新鲜收获的人内皮细胞中，观察到由细胞内粘附分子1（ICAM-1）、isoLG-加合物积累和细胞内GAS 6水平反映的内皮细胞活化程度之间的显著相关性。我们定义了一种以前未被认识到的人内皮细胞和单核细胞的相互作用，促进高血压中AS DC的形成，并显示了GAS 6和Axl信号在免疫细胞和内皮细胞中的关键作用。该通路可能是一个新的治疗靶点，以减少炎症和终末器官损伤的高血压。
There is an intimate relationship between the endothelium and monocytes, and activated endothelial cells promote monocyte transformation to macrophages and dendritic cells (DCs). Recently, a subset of human DCs expressing the receptor tyrosine kinase, Axl and the lectin Siglec-6 has been described and termed AS DCs. We sought to determine if circulating AS DCs are increased in human hypertension and to examine how Axl signaling contributes to this disease. We demonstrated that circulating AS DCs are increased in hypertensive humans compared to normotensive controls. Pulse pressure in humans also correlated with plasma levels of the Axl agonist growth arrest specific 6 (GAS6). Exposure of human endothelial cells to 10% cyclical stretch increased release of the GAS6, promoted Axl signaling and caused AS DC formation; events that were inhibited by blockade of Axl with R428 or by siRNA knockdown of either endothelial GAS6 or Axl. GAS6/Axl signaling in human monocytes potentiated interleukin 1-beta production through NLRP3/caspase-1 and caused accumulation of immunogenic isolevuglandin (isoLG)-protein adducts. In mice, the Axl inhibitor R428 or global deletion of Axl attenuated hypertension and renal inflammation caused by angiotensin II (Ang II) infusion. Bone marrow transplant studies demonstrated a role of both stromal and immunological Axl in Ang II-induced hypertension. Lastly, in freshly harvested human endothelial cells, a striking correlation was observed between the degree of endothelial cell activation as reflected by intracellular adhesion molecule 1 (ICAM-1), isoLG-adduct accumulation and intracellular GAS6 levels. We define a previously unrecognized interaction of human endothelial cells and monocytes that promote formation of AS DCs in hypertension and show a critical role of GAS6 and Axl signaling in both immune cells and endothelial cells. This pathway is potentially a novel therapeutic target to reduce inflammation and end organ damage in hypertension.