Gao Liang, Gülcüler Gülce Sila, Golbach Lieke, Block Helena, Zarbock Alexander, Martin-Villalba Ana
Division of Molecular Neurobiology, German Cancer Research Center, Heidelberg, Germany.
Department of Anesthesiology and Critical Care Medicine, University of Münster, Münster, Germany.
Elife. 2016 Oct 20;5:e18542. doi: 10.7554/eLife.18542.
Integrin activation is crucial for the regulation of leukocyte rolling, adhesion and trans-vessel migration during inflammation and occurs by engagement of myeloid cells through factors presented by inflamed vessels. However, endothelial-dependent mechanisms of myeloid cell recruitment are not fully understood. Here we show using an autoperfused flow chamber assay of whole blood neutrophils and intravital microscopy of the inflamed cremaster muscle that CD95 mediates leukocyte slow rolling, adhesion and transmigration upon binding of CD95-ligand (CD95L) that is presented by endothelial cells. In myeloid cells, CD95 triggers activation of Syk-Btk/PLCγ2/Rap1 signaling that ultimately leads to integrin activation. Excitingly, CD95-deficient myeloid cells exhibit impaired bacterial clearance in an animal model of sepsis induced by cecal ligation and puncture (CLP). Our data identify the cellular and molecular mechanisms underlying the chemoattractant effect of endothelial cell-derived CD95L in induction of neutrophil recruitment and support the use of therapeutic inhibition of CD95's activity in inflammatory diseases.
整合素激活对于炎症过程中白细胞滚动、黏附和跨血管迁移的调节至关重要，它通过炎症血管呈现的因子与髓样细胞结合而发生。然而，髓样细胞募集的内皮依赖性机制尚未完全了解。在这里，我们使用全血中性粒细胞的自灌注流动腔室分析和炎症提睾肌的活体显微镜检查表明，CD95在内皮细胞呈现CD95配体（CD95L）结合后介导白细胞缓慢滚动、黏附和迁移。在髓样细胞中，CD95触发Syk-Btk/PLCγ2/Rap1信号通路的激活，最终导致整合素激活。令人兴奋的是，在盲肠结扎和穿刺（CLP）诱导的脓毒症动物模型中，缺乏CD95的髓样细胞表现出细菌清除受损。我们的数据确定了内皮细胞衍生的CD95L在诱导中性粒细胞募集中趋化作用的细胞和分子机制，并支持在炎症性疾病中使用治疗性抑制CD95活性。
