Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages.
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.
Atabai
Kamran
K
Lung Biology Center, Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
Jame
Sina
S
Azhar
Nabil
N
Kuo
Alex
A
Lam
Michael
M
McKleroy
William
W
Dehart
Greg
G
Rahman
Salman
S
Xia
Dee Dee
DD
Melton
Andrew C
AC
Wolters
Paul
P
Emson
Claire L
CL
Turner
Scott M
SM
Werb
Zena
Z
Sheppard
Dean
D
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
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