title: Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages.
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.
authors.affiliation: Lung Biology Center, Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
authors.forename: Kamran
authors.initials: K
authors.lastname: Atabai
authors.forename: Sina
authors.initials: S
authors.lastname: Jame
authors.forename: Nabil
authors.initials: N
authors.lastname: Azhar
authors.forename: Alex
authors.initials: A
authors.lastname: Kuo
authors.forename: Michael
authors.initials: M
authors.lastname: Lam
authors.forename: William
authors.initials: W
authors.lastname: McKleroy
authors.forename: Greg
authors.initials: G
authors.lastname: Dehart
authors.forename: Salman
authors.initials: S
authors.lastname: Rahman
authors.forename: Dee Dee
authors.initials: DD
authors.lastname: Xia
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Melton
authors.forename: Paul
authors.initials: P
authors.lastname: Wolters
authors.forename: Claire L
authors.initials: CL
authors.lastname: Emson
authors.forename: Scott M
authors.initials: SM
authors.lastname: Turner
authors.forename: Zena
authors.initials: Z
authors.lastname: Werb
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D001483:Base Sequence; D001761:Bleomycin / Q000633:toxicity; D003094:Collagen / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D000070821:Discoidins; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D037102:Lectins / Q000737:chemistry / Q000235:genetics; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008894:Milk Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D017931:DNA Primers; D000070821:Discoidins; D037102:Lectins; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D001761:Bleomycin; D003094:Collagen