title: Targeted deletion of CCR2 impairs deep vein thombosis resolution in a mouse model.
abstract: CCR2 is required for monocyte recruitment in many inflammatory processes, as well as conferring Th1 lymphokine responses. Deep vein thrombosis (DVT) resolution represents a specific inflammatory response whereby the thrombus must be dissolved for restoration of blood flow. Using a stasis model of DVT in the mouse, we investigated the role of CCR2 on DVT resolution. Genetic deletion of CCR2 (CCR2-/-) was associated with larger thrombi at early and later time points, increased thrombus collagen, fewer thrombus monocytes (F4/80), and significantly impaired neovascularization. IL-2 and IFN-gamma were significantly reduced in early CCR2-/- thrombi, whereas MCP-1 was significantly increased, and Th2 lymphokines were unaffected. Supplementation of CCR2-/- mice with IFN-gamma normalized early thrombus resolution without increasing monocyte influx. Neither Ab depletion of IFN-gamma nor genetic deletion of IFN-gamma impaired early DVT resolution. Early fibrinolysis was not impaired in CCR2-/- mice, but a significant reduction in both matrix metalloproteinase (MMP)-2 and MMP-9 activity was observed. However, only MMP-9 activity was restored with administration of IFN-gamma. We conclude that an early CCR2-dependent Th1 lymphokine response predominates in normal DVT resolution, mediates this in part by MMP-9 activation, but is not solely dependent on IFN-gamma.
authors.affiliation: University of Michigan Health System, Ann Arbor, MI 48109, USA. henke@umich.edu
authors.forename: Peter K
authors.initials: PK
authors.lastname: Henke
authors.forename: Charles G
authors.initials: CG
authors.lastname: Pearce
authors.forename: Daria M
authors.initials: DM
authors.lastname: Moaveni
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Moore
authors.forename: Erin M
authors.initials: EM
authors.lastname: Lynch
authors.forename: Christopher
authors.initials: C
authors.lastname: Longo
authors.forename: Manu
authors.initials: M
authors.lastname: Varma
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Dewyer
authors.forename: K Barry
authors.initials: KB
authors.lastname: Deatrick
authors.forename: Gilbert R
authors.initials: GR
authors.lastname: Upchurch
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Wakefield
authors.forename: Cory
authors.initials: C
authors.lastname: Hogaboam
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
mesh_terms: D000818:Animals; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D017353:Gene Deletion; D007958:Leukocyte Count; D008222:Lymphokines / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D020246:Venous Thrombosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
chemical_list: C515335:Ccr2 protein, mouse; D018925:Chemokines; D008222:Lymphokines; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9