Atabai K, Jame S, Azhar N et al.Mfge8 diminishes the severity of tissue fibrosis in mice by binding and targeting collagen for uptake by macrophages. J Clin Invest 119:3713-3722

Lung Biology Center, Cardiovascular Research Institute, UCSF, San Francisco, California, USA.
The Journal of clinical investigation (Impact Factor: 13.22). 11/2009; 119(12):3713-22. DOI: 10.1172/JCI40053
Source: PubMed

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.

Download full-text


Available from: Paul J Wolters, Dec 09, 2014
19 Reads
  • Source
    • "Macrophages also produce the majority of wound-associated VEGF, assuring angiogenesis and restoration of oxygen supply (Knighton et al, 1983). M2 macrophages also produce MMPs and TIMPs that control ECM turnover engulf and digest various ECM components that would promote tissue-damaging M1 macrophage responses (Atabai et al, 2009), and secrete specific chemokines that recruit fibroblasts and regulatory T (T Reg ) cells (Curiel et al, 2004). There is scattered evidence supporting the hypothesis that macrophages interact with progenitor or stem cells, and that this interplay may contribute to repair and remodelling. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Resolution of inflammation is a coordinated and active process aimed at restoration of tissue integrity and function. This review integrates the key molecular and cellular mechanisms of resolution. We describe how abrogation of chemokine signalling blocks continued neutrophil tissue infiltration and how apoptotic neutrophils attract monocytes and macrophages to induce their clearance. Uptake of apoptotic neutrophils by macrophages reprograms macrophages towards a resolving phenotype, a key event to restore tissue homeostasis. Finally, we highlight the therapeutic potential that derives from understanding the mechanisms of resolution.
    EMBO Molecular Medicine 05/2013; 5(5). DOI:10.1002/emmm.201202382 · 8.67 Impact Factor
  • Source
    • "This correlates well with findings that uptake of ECM components appears to be mediated by M2 macrophages. Uptake of these components is mediated by different mannose receptors [27] and by glycoprotein milk fat globule epidermal growth factor 8 (Mfge8) [219]. Mannose receptors of course are a known M2 marker, and for Mfge8 this is unclear. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Macrophages are among the most abundant cells in the respiratory tract, and they can have strikingly different phenotypes within this environment. Our knowledge of the different phenotypes and their functions in the lung is sketchy at best, but they appear to be linked to the protection of gas exchange against microbial threats and excessive tissue responses. Phenotypical changes of macrophages within the lung are found in many respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis. This paper will give an overview of what macrophage phenotypes have been described, what their known functions are, what is known about their presence in the different obstructive and restrictive respiratory diseases (asthma, COPD, pulmonary fibrosis), and how they are thought to contribute to the etiology and resolution of these diseases.
    Mediators of Inflammation 02/2013; 2013(7):769214. DOI:10.1155/2013/769214 · 3.24 Impact Factor
  • Source
    • "Data from an ischemia-reperfusion injury model indicates that MFG-E8 administration protects mice by promoting apoptotic cell engulfment [44]. MFG-E8 may bind lung collagen to facilitate its clearance in pulmonary fibrosis [45]. The role of MFG-E8 in inflammation extends beyond phagocytosis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Apoptotic endothelial cells are an important component of the "response to injury" process. Several atherosclerosis risk factors such as hyperglycemia and oxidized low-density lipoproteins, and immune injuries, such as antibodies and complement, induce endothelial cell apoptosis. While endothelial cell apoptosis is known to affect neighboring vascular wall cell biology, its consequences on macrophage reprogramming are ill defined. In this study, we report that apoptosis of human and mouse endothelial cells triggers the release of milk fat globule-epidermal growth factor 8 (MFG-E8) and reprograms macrophages into an anti-inflammatory cells. We demonstrated that MFG-E8 is released by apoptotic endothelial cells in a caspase-3-dependent manner. When macrophages were exposed to conditioned media from serum-starved apoptotic endothelial cells, they adopt a high anti-inflammatory, low pro-inflammatory cytokine/chemokine secreting phenotype that is lost if MFG-E8 is absent from the media. Macrophage treatment with recombinant MFG-E8 recapitulates the effect of conditioned media. Finally, we showed that MFG-E8-mediated reprogramming of macrophages occurs through increased phosphorylation of signal transducer and activator of transcription-3 (STAT-3). Taken together, our study suggests a key role of MFG-E8 release from apoptotic endothelial cells in macrophage reprogramming and demonstrates the importance of the apoptotic microenvironment in anti-inflammatory macrophage responses.
    PLoS ONE 04/2012; 7(4):e36368. DOI:10.1371/journal.pone.0036368 · 3.23 Impact Factor
Show more