CCN1/CYR61-mediated meticulous patrolling by Ly6C low monocytes fuels vascular inflammation

• Published in: Proceedings of the National Academy of Sciences - PNAS 2016-08, Vol.113 (33)
• Main Authors: Imhof, Beat A., Jemelin, Stephane, Ballet, Romain, Vesin, Christian, Schapira, Marc, Karaca, Melis, Emre, Yalin
• Format: Article
• Language: English
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1607710113

Upon infection, circulating leukocytes leave the bloodstream and migrate into the inflammatory site. Neutrophils are the first leukocytes to be recruited within a few hours, followed by inflammatory lymphocyte antigen 6 complex (Ly6C)-positive monocytes. This study refines the model of the leukocyte recruitment cascade. We demonstrate that upon Toll-like receptor 7/8-mediated vascular inflammation, platelet activation drives the rapid mobilization of Ly6C low monocytes to the luminal side of the endothelium. Accumulated Ly6C low monocytes do not extravasate into the tissue. Instead, they meticulously patrol the endothelium and control the subsequent recruitment of neutrophils. Moreover, we show that endothelium-bound cyteine-rich protein 61 (CYR61)/CYR61 connective tissue growth factor nephroblastoma overexpressed 1 (CCN1) protein provides a molecular support for adequate patrolling of Ly6C low monocytes in the steady state and under inflammatory conditions. 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