Targeted deletion of CCR2 impairs deep vein thombosis resolution in a mouse model

Peter K. Henke, Charles G. Pearce, Daria M. Moaveni, Andrea J. Moore, Erin M. Lynch, Christopher Longo, Manu Varma, Nicholas A. Dewyer, K. Barry Deatrick, Gilbert R. Upchurch, Thomas W. Wakefield, Cory Hogaboam, Steven L. Kunkel

Research output: Contribution to journalArticle

87 Scopus citations

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-γ were significantly reduced in early CCR2-/- thrombi, whereas MCP-1 was significantly increased, and Th2 lymphokines were unaffected. Supplementation of CCR2-/- ice with IFN-γ normalized early thrombus resolution without increasing monocyte influx. Neither Ab depletion of IFN-γ nor genetic deletion of IFN-γ 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-γ. 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-γ.

Original languageEnglish (US)
Pages (from-to)3388-3397
Number of pages10
JournalJournal of Immunology
Volume177
Issue number5
DOIs
StatePublished - Sep 1 2006
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Henke, P. K., Pearce, C. G., Moaveni, D. M., Moore, A. J., Lynch, E. M., Longo, C., Varma, M., Dewyer, N. A., Deatrick, K. B., Upchurch, G. R., Wakefield, T. W., Hogaboam, C., & Kunkel, S. L. (2006). Targeted deletion of CCR2 impairs deep vein thombosis resolution in a mouse model. Journal of Immunology, 177(5), 3388-3397. https://doi.org/10.4049/jimmunol.177.5.3388