Imhof Beat A, Jemelin Stephane, Ballet Romain, Vesin Christian, Schapira Marc, Karaca Melis, Emre Yalin
Department of Pathology and Immunology, University of Geneva, 1205 Geneva, Switzerland;
Department of Physiology and Metabolism, University of Geneva, 1205 Geneva, Switzerland.
Proc Natl Acad Sci U S A. 2016 Aug 16;113(33):E4847-56. doi: 10.1073/pnas.1607710113. Epub 2016 Aug 1.
Inflammation is characterized by the recruitment of leukocytes from the bloodstream. The rapid arrival of neutrophils is followed by a wave of inflammatory lymphocyte antigen 6 complex (Ly6C)-positive monocytes. In contrast Ly6C(low) monocytes survey the endothelium in the steady state, but their role in inflammation is still unclear. Here, using confocal intravital microscopy, we show that upon Toll-like receptor 7/8 (TLR7/8)-mediated inflammation of mesenteric veins, platelet activation drives the rapid mobilization of Ly6C(low) monocytes to the luminal side of the endothelium. After repeatedly interacting with platelets, Ly6C(low) monocytes commit to a meticulous patrolling of the endothelial wall and orchestrate the subsequent arrival and extravasation of neutrophils through the production of proinflammatory cytokines and chemokines. At a molecular level, we show that cysteine-rich protein 61 (CYR61)/CYR61 connective tissue growth factor nephroblastoma overexpressed 1 (CCN1) protein is released by activated platelets and enables the recruitment of Ly6C(low) monocytes upon vascular inflammation. In addition endothelium-bound CCN1 sustains the adequate patrolling of Ly6C(low) monocytes both in the steady state and under inflammatory conditions. Blocking CCN1 or platelets with specific antibodies impaired the early arrival of Ly6C(low) monocytes and abolished the recruitment of neutrophils. These results refine the leukocyte recruitment cascade model by introducing endothelium-bound CCN1 as an inflammation mediator and by demonstrating a role for platelets and patrolling Ly6C(low) monocytes in acute vascular inflammation.
炎症的特征是白细胞从血液中募集。中性粒细胞迅速到达，随后是一波炎症性淋巴细胞抗原6复合物（Ly6C）阳性单核细胞。相比之下，Ly6C（低）单核细胞在稳态下监测内皮，但它们在炎症中的作用仍不清楚。在这里，我们使用共聚焦活体显微镜显示，在肠系膜静脉的Toll样受体7/8（TLR7/8）介导的炎症反应中，血小板活化驱动Ly6C（低）单核细胞迅速迁移到内皮的管腔侧。在与血小板反复相互作用后，Ly6C（低）单核细胞致力于对内皮壁进行细致的巡逻，并通过产生促炎细胞因子和趋化因子来协调随后中性粒细胞的到达和渗出。在分子水平上，我们表明富含半胱氨酸的蛋白61（CYR61）/CYR61结缔组织生长因子肾母细胞瘤过表达蛋白1（CCN1）由活化的血小板释放，并在血管炎症时促使Ly6C（低）单核细胞的募集。此外，内皮结合的CCN1在稳态和炎症条件下都维持Ly6C（低）单核细胞的充分巡逻。用特异性抗体阻断CCN1或血小板会损害Ly6C（低）单核细胞的早期到达，并消除中性粒细胞的募集。这些结果通过引入内皮结合的CCN1作为炎症介质，并证明血小板和巡逻的Ly6C（低）单核细胞在急性血管炎症中的作用，完善了白细胞募集级联模型。
