CCR2-mediated recruitment of fibrocytes to the alveolar space after fibrotic injury.
Bone marrow-derived cells are known to play important roles in repair/regeneration of injured tissues, but their roles in pathological fibrosis are less clear. Here, we report a critical role for the chemokine receptor CCR2 in the recruitment and activation of lung fibrocytes (CD45(+), CD13(+), collagen 1(+), CD34(-)). Lung fibrocytes were isolated in significantly greater numbers from airspaces of fluorescein isothiocyanate-injured CCR2(+/+) mice than from CCR2(-/-) mice. Transplant of CCR2(+/+) bone marrow into CCR2(-/-) recipients restored recruitment of lung fibrocytes and susceptibility to fibrosis. Ex vivo PKH-26-labeled CCR2(+/+) lung fibrocytes also migrated to injured airspaces of CCR2(-/-) recipients in vivo. Isolated lung fibrocytes expressed CCR2 and migrated to CCL2, and CCL2 stimulated collagen secretion by lung fibrocytes. Fibrocytes could transition into fibroblasts in vitro, and this transition was associated with loss of CCR2 expression and enhanced production of collagen 1. This is the first report describing expression of CCR2 on lung fibrocytes and demonstrating that CCR2 regulates both recruitment and activation of these cells after respiratory injury.
Moore
Bethany B
BB
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-0642, USA. bmoore@umich.edu
Kolodsick
Jill E
JE
Thannickal
Victor J
VJ
Cooke
Kenneth
K
Moore
Thomas A
TA
Hogaboam
Cory
C
Wilke
Carol A
CA
Toews
Galen B
GB
D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D016026:Bone Marrow Transplantation; D018893:Bronchoalveolar Lavage; D018826:CD13 Antigens / Q000096:biosynthesis; D019070:Cell Lineage; D002465:Cell Movement; D049109:Cell Proliferation; D002633:Chemotaxis; D003094:Collagen / Q000096:biosynthesis; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005355:Fibrosis; D005434:Flow Cytometry; D007150:Immunohistochemistry; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010100:Oxygen / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
C515335:Ccr2 protein, mouse; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003094:Collagen; D017493:Leukocyte Common Antigens; D018826:CD13 Antigens; D010100:Oxygen
Am J Pathol. 1999 Nov;155(5):1773-9
10550334
Blood. 1998 Oct 1;92(7):2571-80
9746799
Am J Respir Crit Care Med. 2000 Feb;161(2 Pt 1):646-64
10673212
Curr Rheumatol Rep. 2000 Dec;2(6):501-5
11123104
J Immunol. 2001 Jun 15;166(12):7556-62
11390511
J Allergy Clin Immunol. 2001 Jun;107(6):1001-8
11398077
Am J Respir Crit Care Med. 2001 Sep 15;164(6):1025-32
11587991
J Immunol. 2001 Oct 15;167(8):4368-77
11591761
Am J Respir Cell Mol Biol. 2002 Oct;27(4):419-27
12356575
J Immunol. 2003 Jul 1;171(1):380-9
12817021
Am J Dermatopathol. 2003 Aug;25(4):358
12876500
Am J Respir Cell Mol Biol. 2003 Aug;29(2):213-24
12649121
Am J Physiol Lung Cell Mol Physiol. 2003 Sep;285(3):L527-39
12598227
Thorax. 2003 Sep;58(9):772-7
12947136
Am J Respir Cell Mol Biol. 2003 Nov;29(5):537-44
12738687
J Clin Invest. 2004 Jan;113(2):243-52
14722616
Annu Rev Med. 2004;55:395-417
14746528
J Immunol. 2004 Apr 1;172(7):4068-76
15034018
Transplantation. 1992 Nov;54(5):802-8
1359684
Biochem Biophys Res Commun. 1994 Jul 29;202(2):1156-62
8048929
Am J Respir Crit Care Med. 1994 Oct;150(4):967-72
7921471
J Immunol. 1994 Nov 15;153(10):4733-41
7525714
J Biol Chem. 1996 May 17;271(20):11603-7
8662823
Mol Med. 1994 Nov;1(1):71-81
8790603
Am J Pathol. 1997 Mar;150(3):981-91
9060836
J Cutan Pathol. 1997 Feb;24(2):65-9
9162737
Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12053-8
9342361
J Immunol. 1998 Jan 1;160(1):419-25
9551999
J Pharmacol Exp Ther. 2000 Mar;292(3):988-94
10688614