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Blood, 1 June 2006, Vol. 107, No. 11, pp. 4240-4243.
Prepublished online as a Blood First Edition Paper on February 7, 2006; DOI 10.1182/blood-2005-09-3922.
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Submitted October 4, 2005
Accepted January 23, 2006
Deficiency in CCR5 but not CCR1 protects against neointima formation in atherosclerosis-prone mice: involvement of IL-10
Alma Zernecke, Elisa A Liehn, Ji-Liang Gao, William A Kuziel, Philip M Murphy, and Christian Weber*
Institute of Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany; Department of Cardiology, RWTH Aachen University, Aachen, Germany
Institute of Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany
Laboratory of Molecular Immunology, NIAID, Bethesda, Maryland, USA
Protein Design Labs, Fremont, California, USA
* Corresponding author; email: cweber{at}ukaachen.de.
The chemokine RANTES has been implicated in neointimal hyperplasia after arterial injury. We analyzed the differential role of the RANTES receptors CCR1 and CCR5 by genetic deletion in apolipoprotein E-deficient mice. Deficiency in CCR5 significantly reduced neointimal area after arterial wire-injury, associated with a decrease in macrophages, CD3+ T lymphocytes and CCR2+ cells. In contrast, CCR1 deficiency did not affect neointimal area or cell content. Deletion of CCR5 entailed up-regulation of the anti-inflammatory cytokine interleukin-10 in neointimal smooth muscle cells, and its antibody blockade reversed effects in CCR5-/- mice. Conversely, pro-inflammatory interferon- was increased in the neointima of CCR1-/- mice, and its blockade unmasked a reduction in macrophage recruitment. Our data indicate that CCR5 is more crucial than CCR1 for neointimal formation, and that its attenuation in CCR5-/- mice is due to an athero-protective immune response involving interleukin-10. This harbours important implications for targeting of chemokine receptors in vascular remodelling.
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