CX3CL1 up-regulation is associated with recruitment of CX3CR1+ mononuclear phagocytes and T lymphocytes in the lungs during cigarette smoke-induced emphysema.
CX3CR1 is expressed on monocytes, dendritic cells, macrophages, subsets of T lymphocytes, and natural killer cells and functions in diverse capacities such as leukocyte adhesion, migration, and cell survival on ligand binding. Expression of the CX3CL1 gene, whose expression product is the sole ligand for CX3CR1, is up-regulated in human lungs with chronic cigarette smoke-induced obstructive lung disease. At present, it is unknown whether CX3CL1 up-regulation is associated with the recruitment and accumulation of immune cells that express CX3CR1. We show that mice chronically exposed to cigarette smoke up-regulate CX3CL1 gene expression, which is associated with an influx of CX3CR1+ cells in the lungs. The increase in CX3CR1+ cells is primarily comprised of macrophages and T lymphocytes and is associated with the development of emphysema. In alveolar macrophages, cigarette smoke exposure increased the expression of both CX3CR1 and CX3CL1 genes. The inducibility of CX3CR1 expression was not solely dependent on a chronic stimulus because lipopolysaccharide up-regulated CX3CR1 in RAW264.7 cells in vitro and in mononuclear phagocytes in vivo. Our findings suggest a mechanism by which macrophages amplify and promote CX3CR1+ cell accumulation within the lungs during both acute and chronic inflammatory stress. We suggest that one function of the CX3CR1-CX3CL1 pathway is to recruit and sustain divergent immune cell populations implicated in the pathogenesis of cigarette smoke-induced emphysema.
McComb
Jennifer G
JG
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Ranganathan
Mrunalini
M
Liu
Xiang Hong
XH
Pilewski
Joseph M
JM
Ray
Prabir
P
Watkins
Simon C
SC
Choi
Augustine M K
AM
Lee
Janet S
JS
D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D054428:Chemokine CX3CL1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D009504:Neutrophils / Q000187:drug effects; D010586:Phagocytes / Q000187:drug effects / Q000473:pathology*; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D019707:Receptors, Chemokine / Q000235:genetics* / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D017252:CD3 Complex; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; C471885:Cx3cr1 protein, mouse; D008070:Lipopolysaccharides; D019707:Receptors, Chemokine
J Exp Med. 2003 Jun 16;197(12):1701-7
12810688
Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10896-901
9724801
Thorax. 1962 Dec;17(4):320-28
25269161
Am J Respir Crit Care Med. 1999 Aug;160(2):711-7
10430750
Acta Med Okayama. 2007 Apr;61(2):89-98
17471309
Cell. 1997 Nov 14;91(4):521-30
9390561
Am J Respir Crit Care Med. 2002 May 15;165(10):1404-9
12016104
Am J Respir Crit Care Med. 1998 Oct;158(4):1277-85
9769292
Eur J Immunol. 1999 Aug;29(8):2551-9
10458770
Cell Microbiol. 2007 Mar;9(3):738-52
17054437
J Clin Invest. 2003 Feb;111(3):333-40
12569158
Thorax. 1992 Jun;47(6):437-40
1496503
FEBS Lett. 2004 Mar 12;561(1-3):105-10
15013759
Biochem Biophys Res Commun. 1998 Dec 30;253(3):728-32
9918795
J Clin Invest. 1990 Nov;86(5):1496-502
2173721
Am J Respir Crit Care Med. 2007 May 15;175(10):998-1005
17332482
Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8075-80
10869418
Eur J Immunol. 1999 Jun;29(6):1925-32
10382755
J Clin Invest. 2001 May;107(9):1173-81
11342581
Nature. 1997 Feb 13;385(6617):640-4
9024663
J Leukoc Biol. 1993 May;53(5):504-10
8501394
PLoS Med. 2004 Oct;1(1):e8
15526056
Am J Respir Crit Care Med. 1995 Nov;152(5 Pt 1):1666-72
7582312
Rheumatology (Oxford). 2007 Sep;46(9):1422-7
17616549
Carcinogenesis. 1997 Nov;18(11):2035-42
9395199
Proc Natl Acad Sci U S A. 2004 Oct 12;101(41):14895-900
15469929
Am J Respir Cell Mol Biol. 2007 Apr;36(4):409-17
17079780
Am J Pathol. 2003 Dec;163(6):2329-35
14633606
Am J Pathol. 2001 Mar;158(3):855-66
11238035
Clin Microbiol Rev. 2001 Apr;14(2):336-63
11292642
Am J Respir Crit Care Med. 1994 Jul;150(1):238-44
8025756
Immunity. 2003 Jul;19(1):71-82
12871640
Science. 2005 Jan 14;307(5707):254-8
15653504
N Engl J Med. 1974 Oct 10;291(15):755-8
4414996
Am J Respir Crit Care Med. 1998 Mar;157(3 Pt 1):822-6
9517597
Science. 2006 Jan 6;311(5757):83-7
16322423
Nat Neurosci. 2006 Jul;9(7):917-24
16732273
J Biol Chem. 1998 Sep 11;273(37):23799-804
9726990
N Engl J Med. 1994 Apr 7;330(14):975-80
8121461
J Immunol. 2006 Dec 1;177(11):8086-94
17114483
Proc Natl Acad Sci U S A. 2004 Dec 21;101(51):17795-800
15596719
N Engl J Med. 2004 Jun 24;350(26):2645-53
15215480
Am J Physiol Lung Cell Mol Physiol. 2005 Nov;289(5):L731-8
16024722
J Immunol. 2007 Aug 1;179(3):1438-48
17641009
Am J Respir Cell Mol Biol. 2005 May;32(5):367-72
15837726
Am J Respir Crit Care Med. 2004 Nov 1;170(9):974-80
15282203
Am J Respir Crit Care Med. 1999 Nov;160(5 Pt 2):S29-32
10556166
Am J Respir Crit Care Med. 1997 Mar;155(3):852-7
9117016
Am J Physiol Lung Cell Mol Physiol. 2001 Feb;280(2):L203-13
11158998
Carcinogenesis. 1997 Mar;18(3):575-86
9067559
J Clin Invest. 2004 Nov;114(9):1248-59
15520857
Science. 1997 Sep 26;277(5334):2002-4
9302297
J Immunol. 2006 Oct 1;177(7):4350-9
16982869
Lancet. 1997 May 24;349(9064):1498-504
9167458
J Immunol. 2007 Feb 15;178(4):2000-7
17277103
Am J Respir Cell Mol Biol. 1999 Jun;20(6):1100-2
10340927
Mol Cell Biol. 2000 Jun;20(11):4106-14
10805752
Res Exp Med (Berl). 1997;197(1):1-11
9226758
J Immunol. 2000 Jul 1;165(1):397-403
10861077