The role of CCL12 in the recruitment of fibrocytes and lung fibrosis.
We have previously shown that mice that are genetically deficient in the CCR2 gene (CCR2-/- mice) are protected from fluorescein isothiocyanate (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 three ligands for CCR2 in the mouse: CCL2, CCL7, and CCL12. CCL2 and CCL12 are both elevated in the lung after FITC injury, but with different kinetics. CCL2 is maximal at Day 1 and absent by Day 7 after FITC. In contrast, CCL12 peaks at Day 3, but remains elevated through Day 21 after FITC. We now demonstrate that while CCR2-/- mice are protected from FITC-induced 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.
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, 6301 MSRB III, 1150 W. Medical Center Dr., Ann Arbor, 48109-0642, USA. Bmoore@umich.edu
Bethany B
BB
Moore
Lynne
L
Murray
Anuk
A
Das
Carol A
CA
Wilke
Amy B
AB
Herrygers
Galen B
GB
Toews
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D002633:Chemotaxis; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology*; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D007700:Kinetics; D008171:Lung Diseases / Q000139:chemically induced / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics / Q000502:physiology*
C491224:Ccl12 protein, mouse; D005456:Fluorescent Dyes; D018945:Monocyte Chemoattractant Proteins; D016650:Fluorescein-5-isothiocyanate