title: Inflammatory chemokines direct and restrict leukocyte migration within live tissues as glycan-bound gradients.
abstract: Chemokines are essential in many cell migration processes, including the recruitment of leukocytes to sites of infection. In the latter context, chemokines promote leukocyte extravasation into the relevant tissue through a well-studied cascade of events. It is widely believed that chemokines further guide leukocytes within tissues via chemotaxis, the directed migration along gradients of soluble ligands. However, the basic mechanism of chemokine action within tissues has yet to be formally addressed in vivo. We identified a chemokine (zCxcl8) that recruits zebrafish neutrophils to infection loci and analyzed its function directly within interstitial tissues of living larvae. Using noninvasive imaging and a controlled cellular source of zCxcl8, we found that zCxcl8 guides neutrophils in a 2-fold manner: by biasing cell speed according to direction (orthotaxis) and by restricting cell motility near the source. We further show that zCxcl8 establishes tissue-bound gradients in vivo by binding to heparan sulfate proteoglycans (HSPGs). Inhibition of this interaction compromised both directional guidance and restriction of neutrophil motility. Thus, by interacting with extracellular HSPGs, chemokines establish robust surface-bound (haptotactic) gradients that mediate both recruitment and retention of leukocytes at sites of infection.
authors.affiliation: Macrophages and Development of Immunity Unit, Department of Developmental and Stem Cell Biology, Institut Pasteur, Paris, France. milka.sarris@pasteur.fr
authors.forename: Milka
authors.initials: M
authors.lastname: Sarris
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Masson
authors.forename: Damien
authors.initials: D
authors.lastname: Maurin
authors.forename: Lieke M
authors.initials: LM
authors.lastname: Van der Aa
authors.forename: Pierre
authors.initials: P
authors.lastname: Boudinot
authors.forename: Hugues
authors.initials: H
authors.lastname: Lortat-Jacob
authors.forename: Philippe
authors.initials: P
authors.lastname: Herbomel
mesh_terms: D002465:Cell Movement; D018925:Chemokines / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D007962:Leukocytes / Q000166:cytology*; D009504:Neutrophils / Q000378:metabolism*; D011134:Polysaccharides / Q000378:metabolism*
chemical_list: D018925:Chemokines; D018836:Inflammation Mediators; D011134:Polysaccharides