Home LiteratureArticle Details
PMID: 19884654 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages.

The Journal of clinical investigation ·Vol. 119 ·No. 12 ·2009-12-00 ·Pages 3713-22

Atabai K, Jame S, Azhar N, Kuo A, Lam M, McKleroy W, Dehart G, Rahman S, Xia DD, Melton AC, Wolters P, Emson CL, Turner SM, Werb Z, Sheppard D

Abstract

Milk fat globule epidermal growth factor 8 (Mfge8) is a soluble glycoprotein known to regulate inflammation and immunity by mediating apoptotic cell clearance. Since fibrosis can occur as a result of exaggerated apoptosis and inflammation, we set out to investigate the hypothesis that Mfge8 might negatively regulate tissue fibrosis. We report here that Mfge8 does decrease the severity of tissue fibrosis in a mouse model of pulmonary fibrosis; however, it does so not through effects on inflammation and apoptotic cell clearance, but by binding and targeting collagen for cellular uptake through its discoidin domains. Initial analysis revealed that Mfge8-/- mice exhibited enhanced pulmonary fibrosis after bleomycin-induced lung injury. However, they did not have increased inflammation or impaired apoptotic cell clearance after lung injury compared with Mfge8+/+ mice; rather, they had a defect in collagen turnover. Further experiments indicated that Mfge8 directly bound collagen and that Mfge8-/- macrophages exhibited defective collagen uptake that could be rescued by recombinant Mfge8 containing at least one discoidin domain. These data demonstrate a critical role for Mfge8 in decreasing the severity of murine tissue fibrosis by facilitating the removal of accumulated collagen.

MeSH Terms
Animals Antigens, Surface/chemistry,genetics,metabolism Apoptosis Base Sequence Bleomycin/toxicity Collagen/metabolism DNA Primers/genetics Discoidins Disease Models, Animal Extracellular Matrix/metabolism Female Lectins/chemistry,genetics Macrophages, Alveolar/drug effects,metabolism,pathology Male Mice Mice, Knockout Milk Proteins/chemistry,genetics,metabolism Protein Binding Protein Structure, Tertiary Protozoan Proteins/chemistry,genetics Pulmonary Fibrosis/chemically induced,metabolism,pathology Recombinant Proteins/chemistry,genetics,metabolism
Chemicals
Antigens, Surface DNA Primers Discoidins Lectins Mfge8 protein, mouse Milk Proteins Protozoan Proteins Recombinant Proteins Bleomycin Collagen
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Atabai Kamran
Lung Biology Center, Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
Jame Sina
Azhar Nabil
Kuo Alex
Lam Michael
McKleroy William
Dehart Greg
Rahman Salman
Xia Dee Dee
Melton Andrew C
Wolters Paul
Emson Claire L
Turner Scott M
Werb Zena
Sheppard Dean
References (52)
52 references, click to expand
  1. Drug-induced gingival overgrowth--a review.
    Biol Pharm Bull. 2005 Oct;28(10):1817-21 PMID: 16204928
  2. Matrix metalloproteinase dependent and independent collagen degradation.
    Front Biosci. 2006 Sep 01;11:3100-20 PMID: 16720379
  3. The plasminogen activation system in lung disease.
    Curr Drug Targets. 2007 Sep;8(9):1016-29 PMID: 17896953
  4. Role of integrins in regulation of collagen phagocytosis by human fibroblasts.
    J Cell Physiol. 1996 Sep;168(3):695-704 PMID: 8816924
  5. Resolution of lung inflammation by CD44.
    Science. 2002 Apr 5;296(5565):155-8 PMID: 11935029
  6. Milk fat globule EGF-8 promotes melanoma progression through coordinated Akt and twist signaling in the tumor microenvironment.
    Cancer Res. 2008 Nov 1;68(21):8889-98 PMID: 18974133
  7. Overexpression of MMP9 in macrophages attenuates pulmonary fibrosis induced by bleomycin.
    Int J Biochem Cell Biol. 2007;39(12):2324-38 PMID: 17702637
  8. Pulmonary fibrosis: searching for model answers.
    Am J Respir Cell Mol Biol. 2005 Jul;33(1):9-13 PMID: 15964990
  9. Idiopathic pulmonary fibrosis.
    N Engl J Med. 2001 Aug 16;345(7):517-25 PMID: 11519507
  10. Essential role for MFG-E8 as ligand for alphavbeta5 integrin in diurnal retinal phagocytosis.
    Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12005-10 PMID: 17620600
  11. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry.
    Circ Res. 2003 May 2;92(8):827-39 PMID: 12730128
  12. New functions for the matrix metalloproteinases in cancer progression.
    Nat Rev Cancer. 2002 Mar;2(3):161-74 PMID: 11990853
  13. Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis.
    J Clin Invest. 1999 Jul;104(1):13-9 PMID: 10393694
  14. Global analysis of gene expression in pulmonary fibrosis reveals distinct programs regulating lung inflammation and fibrosis.
    Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1778-83 PMID: 10677534
  15. Identification of a factor that links apoptotic cells to phagocytes.
    Nature. 2002 May 9;417(6885):182-7 PMID: 12000961
  16. Metalloproteinase and growth factor interactions: do they play a role in pulmonary fibrosis?
    Am J Physiol Lung Cell Mol Physiol. 2002 Jul;283(1):L1-11 PMID: 12060555
  17. Activation of the alpha7 nAChR reduces acid-induced acute lung injury in mice and rats.
    Am J Respir Cell Mol Biol. 2007 Aug;37(2):186-92 PMID: 17431097
  18. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice.
    Science. 2004 May 21;304(5674):1147-50 PMID: 15155946
  19. MFG-E8-mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSF.
    J Clin Invest. 2007 Jul;117(7):1902-13 PMID: 17557120
  20. Gelatinase B is required for alveolar bronchiolization after intratracheal bleomycin.
    Am J Pathol. 2000 Aug;157(2):525-35 PMID: 10934155
  21. The urokinase receptor (uPAR) and the uPAR-associated protein (uPARAP/Endo180): membrane proteins engaged in matrix turnover during tissue remodeling.
    Biol Chem. 2004 Feb;385(2):103-36 PMID: 15101555
  22. Extracellular matrix in normal and fibrotic human lungs.
    Am Rev Respir Dis. 1985 Feb;131(2):281-9 PMID: 3882034
  23. Molecular analysis of collagen binding by the human discoidin domain receptors, DDR1 and DDR2. Identification of collagen binding sites in DDR2.
    J Biol Chem. 2003 May 9;278(19):16761-9 PMID: 12611880
  24. The significance of cathepsins, thrombin and aminopeptidase in diffuse interstitial lung diseases.
    J Med Invest. 2005 Feb;52(1-2):93-100 PMID: 15751279
  25. Measurement of protein turnover rates by heavy water labeling of nonessential amino acids.
    Biochim Biophys Acta. 2006 May;1760(5):730-44 PMID: 16567052
  26. Phagocytosis and intracellular digestion of collagen, its role in turnover and remodelling.
    Histochem J. 1996 Apr;28(4):229-45 PMID: 8762055
  27. Myofibroblasts and their role in lung collagen gene expression during pulmonary fibrosis. A combined immunohistochemical and in situ hybridization study.
    Am J Pathol. 1994 Jul;145(1):114-25 PMID: 7518191
  28. Intracellular collagen in the nonpregnant and IUD-containing rat uterus.
    Anat Rec. 1977 Feb;187(2):241-7 PMID: 557912
  29. Cellular and molecular mechanisms of fibrosis.
    J Pathol. 2008 Jan;214(2):199-210 PMID: 18161745
  30. Lactadherin promotes VEGF-dependent neovascularization.
    Nat Med. 2005 May;11(5):499-506 PMID: 15834428
  31. Mapping of epitopes in discoidin domain receptor 1 critical for collagen binding.
    J Biol Chem. 2001 Dec 7;276(49):45952-8 PMID: 11598108
  32. The discoidin domain receptor tyrosine kinases are activated by collagen.
    Mol Cell. 1997 Dec;1(1):13-23 PMID: 9659899
  33. Membrane type-matrix metalloproteinases in idiopathic pulmonary fibrosis.
    Sarcoidosis Vasc Diffuse Lung Dis. 2006 Mar;23(1):13-21 PMID: 16933466
  34. Neutrophil response following intratracheal instillation of collagen peptides into rat lungs.
    Exp Lung Res. 1988;14(4):549-63 PMID: 3208719
  35. The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis.
    Cell. 1999 Feb 5;96(3):319-28 PMID: 10025398
  36. A critical role for the membrane-type 1 matrix metalloproteinase in collagen phagocytosis.
    Mol Biol Cell. 2006 Nov;17(11):4812-26 PMID: 16971509
  37. IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice.
    J Clin Invest. 2007 Dec;117(12):3786-99 PMID: 17992263
  38. Discoidin domain receptor 1 is activated independently of beta(1) integrin.
    J Biol Chem. 2000 Feb 25;275(8):5779-84 PMID: 10681566
  39. Cyclosporine-induced gingival overgrowth: an ultrastructural stereologic study.
    Oral Surg Oral Med Oral Pathol. 1988 Feb;65(2):186-90 PMID: 3422723
  40. Identification of mouse sperm SED1, a bimotif EGF repeat and discoidin-domain protein involved in sperm-egg binding.
    Cell. 2003 Aug 22;114(4):405-17 PMID: 12941270
  41. Phagocytosis and digestion of collagen by gingival fibroblasts in vivo: a study of serial sections.
    J Ultrastruct Res. 1981 Oct;77(1):1-36 PMID: 7299906
  42. Accumulation of MFG-E8/lactadherin on exosomes from immature dendritic cells.
    Blood Cells Mol Dis. 2005 Sep-Oct;35(2):81-8 PMID: 15982908
  43. Role of interleukin-6 in bleomycin-induced lung inflammatory changes in mice.
    Am J Respir Cell Mol Biol. 2008 May;38(5):566-71 PMID: 18096870
  44. Mfge8 is critical for mammary gland remodeling during involution.
    Mol Biol Cell. 2005 Dec;16(12):5528-37 PMID: 16195353
  45. A novel peptide CXCR ligand derived from extracellular matrix degradation during airway inflammation.
    Nat Med. 2006 Mar;12(3):317-23 PMID: 16474398
  46. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak.
    Nat Med. 2008 Jan;14(1):45-54 PMID: 18066075
  47. Idiopathic fibrosing alveolitis: a review with emphasis on ultrastructural and immunohistochemical features.
    Ultrastruct Pathol. 1985;9(3-4):345-72 PMID: 2418565
  48. Measurement of liver collagen synthesis by heavy water labeling: effects of profibrotic toxicants and antifibrotic interventions.
    Am J Physiol Gastrointest Liver Physiol. 2007 Jun;292(6):G1695-705 PMID: 17347453
  49. Extracellular collagenases and the endocytic receptor, urokinase plasminogen activator receptor-associated protein/Endo180, cooperate in fibroblast-mediated collagen degradation.
    J Biol Chem. 2007 Sep 14;282(37):27037-27045 PMID: 17623673
  50. Increased type I procollagen mRNA transcripts in the lungs of mice during the development of bleomycin-induced fibrosis.
    Eur Respir J. 1994 Nov;7(11):1938-43 PMID: 7533103
  51. Mechanisms of bleomycin-induced lung damage.
    Arch Toxicol. 1991;65(2):81-94 PMID: 1711838
  52. The effect of transforming growth factor-beta on cell proliferation and collagen formation by lung fibroblasts.
    J Biol Chem. 1987 Mar 15;262(8):3897-902 PMID: 3493244
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
1558-8238
DOI
10.1172/JCI40053
Published
2009-12-00
Epub
2009-00-02
Pages
3713-22
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC2786804
Subset
IM
Grants
NHLBI NIH HHS · R37 HL053949 · United States
NHLBI NIH HHS · HL53949 · United States
NCRR NIH HHS · S10 RR023443 · United States
NHLBI NIH HHS · R01 HL053949 · United States
NHLBI NIH HHS · HL083950 · United States
NIAID NIH HHS · AI024674 · United States
NIAID NIH HHS · R01 AI024674 · United States
NHLBI NIH HHS · HL083985 · United States
NIAID NIH HHS · R37 AI024674 · United States
NIAID NIH HHS · P01 AI053194 · United States
NHLBI NIH HHS · HL66600 · United States
NHLBI NIH HHS · K08 HL083985 · United States
NHLBI NIH HHS · U01 HL066600 · United States
NHLBI NIH HHS · HL64353 · United States
NHLBI NIH HHS · R01 HL083950 · United States
NIAID NIH HHS · P01 AI053194-050004 · United States
NIAID NIH HHS · AI053194 · United States
External Links
PubMed source DOI: 10.1172/JCI40053 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2