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Published ahead of print on March 16, 2006, doi:10.1165/rcmb.2005-0239OC

Am. J. Respir. Cell Mol. Biol., Volume 35, Number 2, August 2006, 175-181

A more recent version of this article appeared on August 1, 2006
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Submitted on June 30, 2005
Revised on March 14, 2006

The Role of CCL12 in the Recruitment of Fibrocytes and Lung Fibrosis

Bethany B Moore1*, Lynne Murray2, Anuk Das2, Carol A Wilke1, Amy B Herrygers1, and Galen B Toews1

1 Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA, 2 Department of Immunobiology, Centocor Inc., Radnor, PA, USA

* To whom correspondence should be addressed. E-mail: bmoore{at}umich.edu.

We have previously shown that mice which are genetically deficient in the CCR2 gene (CCR2-/- mice) are protected from FITC-induced lung fibrosis. Protection from fibrosis correlated with impaired recruitment of fibrocytes (bone marrow-derived cells which share both leukocyte and mesenchymal markers). There are 3 ligands for CCR2 in the mouse; CCL2, CCL7 and CCL12. CCL2 and CCL12 are both elevated in the lung following FITC injury but with different kinetics. CCL2 is maximal at day 1 and absent by day 7 post-FITC. In contrast, CCL12 peaks at day 3, but remains elevated through day 21 post-FITC. We now demonstrate that while CCR2-/- mice are protected from FITC-fibrosis, CCL2-/- mice are not. CCL2-/- mice are able to recruit fibrocytes to FITC-injured airspaces unlike CCR2-/- mice. Adoptive transfer of CCR2-expressing fibrocytes augments FITC-induced fibrosis in both wild-type and CCR2-/- mice suggesting that these cells play a pathogenic role in the disease process. Both CCL2 and CCL12 are chemotactic for fibrocytes. However, neutralization of CCL12 in wild-type mice significantly protects from FITC-induced fibrosis whereas neutralization of CCL2 was less effective. Thus, CCL12 is likely the CCR2 ligand responsible for driving fibroproliferation in the mouse. As murine CCL12 is homologous to human CCL2, we suggest that the pathobiology of murine CCL12 in fibroproliferation may correlate to human CCL2 biology.




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