Lrp5/β-Catenin Signaling Controls Lung Macrophage Differentiation and Inhibits Resolution of Fibrosis.
Previous studies established that attenuating Wnt/β-catenin signaling limits lung fibrosis in the bleomycin mouse model of this disease, but the contribution of this pathway to distinct lung cell phenotypes relevant to tissue repair and fibrosis remains incompletely understood. Using microarray analysis, we found that bleomycin-injured lungs from mice that lack the Wnt coreceptor low density lipoprotein receptor-related protein 5 (Lrp5) and exhibit reduced fibrosis showed enrichment for pathways related to extracellular matrix processing, immunity, and lymphocyte proliferation, suggesting the contribution of an immune-matrix remodeling axis relevant to fibrosis. Activation of β-catenin signaling was seen in lung macrophages using the β-catenin reporter mouse, Axin2+/LacZ. Analysis of lung immune cells by flow cytometry after bleomycin administration revealed that Lrp5-/-lungs contained significantly fewer Siglec Flowalveolar macrophages, a cell type previously implicated as positive effectors of fibrosis. Macrophage-specific deletion of β-catenin in CD11ccre;β-cateninfloxmice did not prevent development of bleomycin-induced fibrosis but facilitated its resolution by 8 weeks. In a nonresolving model of fibrosis, intratracheal administration of asbestos in Lrp5-/-mice also did not prevent the development of fibrosis but hindered the progression of fibrosis in asbestos-treated Lrp5-/-lungs, phenocopying the findings in bleomycin-treated CD11ccre;β-cateninfloxmice. Activation of β-catenin signaling using lithium chloride resulted in worsened fibrosis in wild-type mice, further supporting that the effects of loss of Lrp5 are directly mediated by Wnt/β-catenin signaling. Together, these data suggest that lung myeloid cells are responsive to Lrp5/β-catenin signaling, leading to differentiation of an alveolar macrophage subtype that antagonizes the resolution of lung fibrosis.
1 Division of Pulmonary and Critical Care Medicine.
Joseph A
JA
Sennello
1 Division of Pulmonary and Critical Care Medicine.
Alexander V
AV
Misharin
1 Division of Pulmonary and Critical Care Medicine.
Annette S
AS
Flozak
2 Division of Allergy and Immunology, and.
Sergejs
S
Berdnikovs
1 Division of Pulmonary and Critical Care Medicine.
Paul
P
Cheresh
3 Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
John
J
Varga
1 Division of Pulmonary and Critical Care Medicine.
David W
DW
Kamp
1 Division of Pulmonary and Critical Care Medicine.
G R Scott
GR
Budinger
1 Division of Pulmonary and Critical Care Medicine.
Cara J
CJ
Gottardi
1 Division of Pulmonary and Critical Care Medicine.
Anna P
http://orcid.org/0000-0001-9998-297X
AP
Lam
D000818:Animals; D001761:Bleomycin; D002454:Cell Differentiation; D005109:Extracellular Matrix / Q000378:metabolism; D007109:Immunity; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000378:metabolism*; D008168:Lung / Q000473:pathology*; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D016676:Macrophages, Alveolar / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D063265:Sialic Acid Binding Immunoglobulin-like Lectins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
D060492:Low Density Lipoprotein Receptor-Related Protein-5; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D051176:beta Catenin; D001761:Bleomycin
Lrp5; alveolar macrophage; bleomycin; lung fibrosis; β-catenin
Nat Med. 2011 Jun;17(6):684-91
21602802
J Biol Chem. 2003 Oct 10;278(41):40231-8
12885771
J Toxicol Environ Health A. 2004 Sep 10;67(17):1391-406
15371238
Mol Cell Biol. 2002 Feb;22(4):1172-83
11809808
J Immunol. 2013 Apr 1;190(7):3447-57
23467934
Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):14973-8
11752446
Immunity. 2013 Jan 24;38(1):79-91
23273845
Cell Commun Signal. 2014 Apr 26;12:29
24767605
J Immunol. 2007 Apr 15;178(8):5288-95
17404313
Am Rev Respir Dis. 1985 Jan;131(1):144-9
3966702
PLoS One. 2013 Oct 21;8(10):e76451
24204629
Am J Pathol. 2003 May;162(5):1393-7
12707021
JAMA. 2008 Mar 19;299(11):1277-90
18349089
J Biol Chem. 2011 May 20;286(20):17435-44
21398522
Cancer Res. 2013 Mar 15;73(6):1721-32
23345161
Science. 2010 Aug 13;329(5993):849-53
20705860
Nat Med. 2004 Jan;10(1):55-63
14702635
J Cell Sci. 2013 Dec 15;126(Pt 24):5598-609
24101723
Am J Physiol. 1998 Dec;275(6 Pt 1):L1208-18
9843859
Am J Pathol. 1986 Feb;122(2):205-11
3946556
Nat Med. 2010 Sep;16(9):1009-17
20818376
Am J Respir Crit Care Med. 2011 Sep 1;184(5):569-81
21680953
Eur J Immunol. 2004 Apr;34(4):1175-84
15048729
Environ Res. 1985 Apr;36(2):314-26
2983976
J Biol Chem. 2012 Feb 10;287(7):5164-72
22203675
J Cell Sci. 2013 Nov 1;126(Pt 21):4974-84
24006258
Nature. 2003 May 22;423(6938):409-14
12717450
Annu Rev Cell Dev Biol. 2004;20:781-810
15473860
Am J Respir Crit Care Med. 2014 Jul 15;190(2):185-95
24921217
Nat Med. 2012 Mar 04;18(4):572-9
22388089
Annu Rev Pathol. 2013 Jan 24;8:241-76
23092186
Nature. 2013 Apr 25;496(7446):445-55
23619691
Nat Rev Immunol. 2009 Apr;9(4):259-70
19282852
J Biol Chem. 2012 Mar 2;287(10 ):7026-38
22241478
Nat Genet. 2009 Nov;41(11):1199-206
19801982
Am J Respir Crit Care Med. 2012 Mar 1;185(5):537-46
22095546
Am J Physiol Lung Cell Mol Physiol. 2009 Nov;297(5):L1002-11
19734317
Am J Respir Crit Care Med. 2011 Sep 1;184(5):547-60
21471090
J Clin Invest. 2014 Jun;124(6):2599-610
24837430
Eur J Endocrinol. 2011 Jan;164(1):123-31
20926594
Am J Respir Cell Mol Biol. 2006 Aug;35(2):175-81
16543609
N Engl J Med. 2008 May 29;358(22):2355-65
18445777
Am J Respir Crit Care Med. 2014 Oct 15;190(8):867-78
25090037
PLoS Med. 2008 Mar 4;5(3):e62
18318599
PLoS One. 2013 Sep 02;8(9):e73279
24023851
Cytokine. 2003 Dec 21;24(6):266-76
14609568
Am J Respir Cell Mol Biol. 2012 Dec;47(6):879-87
23043088
Immunity. 2013 Aug 22;39(2):298-310
23954131
Am J Respir Cell Mol Biol. 2011 Nov;45(5):915-22
21454805
Am J Physiol. 1995 Sep;269(3 Pt 1):L318-25
7573464
J Biol Chem. 2010 Jan 29;285(5):3157-67
19933277
J Mol Cell Cardiol. 2016 Jan;90:146-56
26666179
Mol Cell Biol. 2002 Feb;22(4):1184-93
11809809
Am J Respir Cell Mol Biol. 2013 Oct;49(4):503-10
23672262
Am J Respir Cell Mol Biol. 2013 Jul;49(1):47-57
23470623
Am J Physiol Lung Cell Mol Physiol. 2013 May 1;304(9):L593-601
23457188