Targeted deletion of CCR2 impairs deep vein thombosis resolution in a mouse model.
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.
Henke
Peter K
PK
University of Michigan Health System, Ann Arbor, MI 48109, USA. henke@umich.edu
Pearce
Charles G
CG
Moaveni
Daria M
DM
Moore
Andrea J
AJ
Lynch
Erin M
EM
Longo
Christopher
C
Varma
Manu
M
Dewyer
Nicholas A
NA
Deatrick
K Barry
KB
Upchurch
Gilbert R
GR
Wakefield
Thomas W
TW
Hogaboam
Cory
C
Kunkel
Steven L
SL
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*
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