Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages
Open Access
- 1 December 2009
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 119 (12), 3713-3722
- https://doi.org/10.1172/jci40053
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.Keywords
This publication has 53 references indexed in Scilit:
- Cellular and molecular mechanisms of fibrosisThe Journal of Pathology, 2007
- IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in miceJCI Insight, 2007
- Activation of the α7 nAChR Reduces Acid-Induced Acute Lung Injury in Mice and RatsAmerican Journal of Respiratory Cell and Molecular Biology, 2007
- Essential role for MFG-E8 as ligand for αvβ5 integrin in diurnal retinal phagocytosisProceedings of the National Academy of Sciences, 2007
- MFG-E8–mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSFJCI Insight, 2007
- A Critical Role for the Membrane-type 1 Matrix Metalloproteinase in Collagen PhagocytosisMolecular Biology of the Cell, 2006
- The urokinase receptor (uPAR) and the uPAR-associated protein (uPARAP/ Endo180): membrane proteins engaged in matrix turnover during tissue remodelingBiological Chemistry, 2004
- Identification of a factor that links apoptotic cells to phagocytesNature, 2002
- New functions for the matrix metalloproteinases in cancer progressionNature Reviews Cancer, 2002
- Intracellular collagen in the nonpregnant and IUD‐containing rat uterusThe Anatomical Record, 1977