title: CCN1/CYR61-mediated meticulous patrolling by Ly6Clow monocytes fuels vascular inflammation.
abstract: 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.
authors.affiliation: Department of Pathology and Immunology, University of Geneva, 1205 Geneva, Switzerland;
authors.forename: Beat A
authors.initials: BA
authors.lastname: Imhof
authors.affiliation: Department of Pathology and Immunology, University of Geneva, 1205 Geneva, Switzerland;
authors.forename: Stephane
authors.initials: S
authors.lastname: Jemelin
authors.affiliation: Department of Pathology and Immunology, University of Geneva, 1205 Geneva, Switzerland;
authors.forename: Romain
authors.initials: R
authors.lastname: Ballet
authors.affiliation: Department of Physiology and Metabolism, University of Geneva, 1205 Geneva, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Vesin
authors.affiliation: Department of Pathology and Immunology, University of Geneva, 1205 Geneva, Switzerland;
authors.forename: Marc
authors.initials: M
authors.lastname: Schapira
authors.affiliation: Department of Physiology and Metabolism, University of Geneva, 1205 Geneva, Switzerland.
authors.forename: Melis
authors.initials: M
authors.lastname: Karaca
authors.affiliation: Department of Pathology and Immunology, University of Geneva, 1205 Geneva, Switzerland; yalinemre@gmail.com.
authors.forename: Yalin
authors.initials: Y
authors.lastname: Emre
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000032:analysis*; D001792:Blood Platelets / Q000502:physiology; D002465:Cell Movement; D055515:Cysteine-Rich Protein 61 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology; D051199:Toll-Like Receptor 7 / Q000502:physiology; D051200:Toll-Like Receptor 8 / Q000502:physiology; D014657:Vasculitis / Q000209:etiology*
chemical_list: D000950:Antigens, Ly; C491850:CCN1 protein, mouse; D055515:Cysteine-Rich Protein 61; C494192:Ly-6C antigen, mouse; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8
keywords: CCN1; inflammation; monocyte; neutrophil; platelet