title: Discoidin domain receptor 2 regulates neutrophil chemotaxis in 3D collagen matrices.
abstract: Neutrophils express a variety of collagen receptors at their surface, yet their functional significance remains unclear. Although integrins are essential for neutrophil adhesion and migration on 2-dimensional (2D) surfaces, neutrophils can compensate for the absence of integrins in 3-dimensional (3D) lattices. In contrast, we demonstrate that the inhibition of the tyrosine-kinase collagen receptor discoidin domain receptor 2 (DDR2) has no impact on human primary neutrophil migration on 2D surfaces but is an important regulator of neutrophil chemotaxis in 3D collagen matrices. In this context, we show that DDR2 activation specifically regulates the directional migration of neutrophils in chemoattractant gradients. We further demonstrate that DDR2 regulates directionality through its ability to increase secretion of metalloproteinases and local generation of collagen-derived chemotactic peptide gradients. Our findings highlight the importance of collagen-derived extracellular signaling during neutrophil chemotaxis in 3D matrices.
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Philippe V
authors.initials: PV
authors.lastname: Afonso
authors.forename: Colin P
authors.initials: CP
authors.lastname: McCann
authors.forename: Senta M
authors.initials: SM
authors.lastname: Kapnick
authors.forename: Carole A
authors.initials: CA
authors.lastname: Parent
mesh_terms: D054441:Cell Migration Assays, Leukocyte / Q000379:methods; D016764:Cell Polarity / Q000187:drug effects; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D003094:Collagen / Q000737:chemistry / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D000070818:Discoidin Domain Receptors; D005109:Extracellular Matrix / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D061251:Primary Cell Culture; D011480:Protease Inhibitors / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D011975:Receptors, Mitogen / Q000378:metabolism / Q000502:physiology*; D046509:Tissue Culture Techniques / Q000379:methods; D054457:Tissue Scaffolds / Q000737:chemistry
chemical_list: D004151:Dipeptides; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D011975:Receptors, Mitogen; D003094:Collagen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; D020778:Matrix Metalloproteinase 2