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Anti-Inflammatory Role of MFG-E8 in the Intestinal Tract

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MFG-E8 and Inflammation

Abstract

Engulfment of apoptosis cells is an essential process for maintaining immune homeostasis, which is regulated by a variety of molecules. Milk fat globule-epidermal growth factor-factor 8 (MFG-E8), a secreted glycoprotein, enhances engulfment of apoptotic cells by forming a link between phosphatidylserine on apoptotic cells and αvβ3-integrin on phagocytes. MFG-E8-mediated engulfment of apoptotic cells contributes to preserving the intestinal physiological condition. In addition to this scavenging function, MFG-E8 also directly regulates the functions of macrophages and intestinal epithelial cells via αvβ3-integrin on their cell surfaces, which attenuates inflammation and enhances regeneration of injured intestinal tissues. This chapter highlights recent findings regarding the role of MEG-E8 in the intestinal tract and demonstrates its therapeutic potential for gut inflammatory diseases.

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References

  1. Krysko DV, D’Herde K, Vandenabeele P (2006) Clearance of apoptotic and necrotic cells and its immunological consequences. Apoptosis 11:1709–1726

    Article  PubMed  Google Scholar 

  2. Gregory CD, Devitt A (2004) The macrophage and the apoptotic cell: an innate immune interaction viewed simplistically. Immunology 113:1–14

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  3. Lauber K, Blumenthal SG, Waibel M et al (2004) Clearance of apoptotic cells: getting rid of the corpses. Mol Cell 14:277–287

    Article  PubMed  CAS  Google Scholar 

  4. Savill J, Fadok V (2000) Corpse clearance defines the meaning of cell death. Nature 407:784–788

    Article  PubMed  CAS  Google Scholar 

  5. Stubbs JD, Lekutis C, Singer KL et al (1990) cDNA cloning of a mouse mammary epithelial cell surface protein reveals the existence of epidermal growth factor-like domains linked to factor VIII-like sequences. Proc Natl Acad Sci U S A 87:8417–8421

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  6. Hanayama R, Tanaka M, Miwa K et al (2004) Expression of developmental endothelial locus-1 in a subset of macrophages for engulfment of apoptotic cells. J Immunol 172:3876–3882

    Article  PubMed  CAS  Google Scholar 

  7. Miyasaka K, Hanayama R, Tanaka M et al (2004) Expression of milk fat globule epidermal growth factor 8 in immature dendritic cells for engulfment of apoptotic cells. Eur J Immunol 34:1414–1422

    Article  PubMed  CAS  Google Scholar 

  8. Hanayama R, Tanaka M, Miwa K et al (2002) Identification of a factor that links apoptotic cells to phagocytes. Nature 417:182–187

    Article  PubMed  CAS  Google Scholar 

  9. Asano K, Miwa M, Miwa K et al (2004) Masking of phosphatidylserine inhibits apoptotic cell engulfment and induces autoantibody production in mice. J Exp Med 200:459–467

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  10. Hanayama R, Tanaka M, Miyasaka K et al (2004) Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304:1147–1150

    Article  PubMed  CAS  Google Scholar 

  11. Komura H, Miksa M, Wu R et al (2009) Milk fat globule epidermal growth factor-factor VIII is down-regulated in sepsis via the lipopolysaccharide-CD14 pathway. J Immunol 182:581–587

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  12. Ait-Oufella H, Kinugawa K, Zoll J et al (2007) Lactadherin deficiency leads to apoptotic cell accumulation and accelerated atherosclerosis in mice. Circulation 115:2168–2177

    Article  PubMed  CAS  Google Scholar 

  13. Thorp E, Tabas I (2009) Mechanisms and consequences of efferocytosis in advanced atherosclerosis. J Leukoc Biol 86:1089–1095

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  14. Fuller AD, Van Eldik LJ (2008) MFG-E8 regulates microglial phagocytosis of apoptotic neurons. J Neuroimmune Pharmacol 3:246–256

    Article  PubMed Central  PubMed  Google Scholar 

  15. Aziz MM, Ishihara S, Mishima Y et al (2009) MFG-E8 attenuates intestinal inflammation in murine experimental colitis by modulating osteopontin-dependent alphavbeta3 integrin signaling. J Immunol 182:7222–7232

    Article  PubMed  CAS  Google Scholar 

  16. Kusunoki R, Ishihara S, Sonoyama H et al (2012) Role of Milk fat globule epidermal growth factor-8 in intestinal inflammation and carcinogenesis. Gut 61(Suppl 3):A54

    Google Scholar 

  17. Bu HF, Zuo XL, Wang X et al (2007) Milk fat globule-EGF factor 8/lactadherin plays a crucial role in maintenance and repair of murine intestinal epithelium. J Clin Invest 117:3673–3683

    PubMed Central  PubMed  CAS  Google Scholar 

  18. Chogle A, Bu HF, Wang X et al (2011) Milk fat globule-EGF factor 8 is a critical protein for healing of dextran sodium sulfate-induced acute colitis in mice. Mol Med 17:502–507

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  19. Otani A, Ishihara S, Aziz MM et al (2012) Intrarectal administration of MFG-E8 protein ameliorates murine experimental colitis by inhibiting Src-mediated NF-κB activation in intestinal epithelial cells. Int J Mol Med 29:349–356

    Google Scholar 

  20. Wu R, Chaung WW, Zhou M et al (2010) Milk fat globule EGF factor 8 attenuates sepsis-induced apoptosis and organ injury in alcohol-intoxicated rats. Alcohol Clin Exp Res 34:1625–1633

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  21. Cui T, Miksa M, Wu R et al (2010) Milk fat globule epidermal growth factor 8 attenuates acute lung injury in mice after intestinal ischemia and reperfusion. Am J Respir Crit Care Med 181:238–246

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  22. Ajakaiye MA, Jacob A, Wu R et al (2012) Recombinant human MFG-E8 attenuates intestinal injury and mortality in severe whole body irradiation in rats. PLoS One 7:e46540

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  23. Ishihara S, Aziz MM, Yuki T et al (2009) Inflammatory bowel disease: review from the aspect of genetics. J Gastroenterol 44:1097–1108

    Article  PubMed  Google Scholar 

  24. Ogura Y, Bonen DK, Inohara N et al (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603–606

    Article  PubMed  CAS  Google Scholar 

  25. Saitoh T, Fujita N, Jang MH et al (2008) Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456:264–268

    Article  PubMed  CAS  Google Scholar 

  26. Brant SR (2013) Promises, delivery, and challenges of inflammatory bowel disease risk gene discovery. Clin Gastroenterol Hepatol 11:22–26

    Article  PubMed  Google Scholar 

  27. Zhao QJ, Yu YB, Zuo XL et al (2012) Milk fat globule-epidermal growth factor 8 is decreased in intestinal epithelium of ulcerative colitis patients and thereby causes increased apoptosis and impaired wound healing. Mol Med 18:497–506

    PubMed Central  PubMed  CAS  Google Scholar 

  28. Aziz MM, Ishihara S, Rumi MA et al (2008) Prolactin induces MFG-E8 production in macrophages via transcription factor C/EBPbeta-dependent pathway. Apoptosis 13(5):609–620

    Article  PubMed  CAS  Google Scholar 

  29. Jinushi M, Nakazaki Y, Dougan M, Carrasco DR, Mihm M, Dranoff G (2007) MFG-E8-mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSF. J Clin Invest 117:1902–1913

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  30. Miksa M, Amin D, Wu R, Ravikumar TS, Wang P (2007) Fractalkine-induced MFG-E8 leads to enhanced apoptotic cell clearance by macrophages. Mol Med 13:553–560

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  31. Mukundan L, Odegaard JI, Morel CR et al (2009) PPAR-delta senses and orchestrates clearance of apoptotic cells to promote tolerance. Nat Med 15:1266–1272

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  32. Goldberg GS, Bechberger JF, Tajima Y et al (2000) Connexin43 suppresses MFG-E8 while inducing contact growth inhibition of glioma cells. Cancer Res 20:6018–6026

    Google Scholar 

  33. Lauber K, Keppeler H, Munoz LE et al (2013) Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids. Cell Death Differ 20:1230–1240

    Article  PubMed  CAS  Google Scholar 

  34. Mishiro T, Kusunoki R, Otani A et al (2013) Butyric acid attenuates intestinal inflammation in murine DSS-induced colitis model via milk fat globule-EGF factor 8. Lab Invest 93:834–843

    Article  PubMed  CAS  Google Scholar 

  35. Silvestre JS, Théry C, Hamard G et al (2005) Lactadherin promotes VEGF-dependent neovascularization. Nat Med 11:499–506

    Article  PubMed  CAS  Google Scholar 

  36. Jinushi M, Chiba S, Yoshiyama H et al (2011) Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells. Proc Natl Acad Sci U S A 108:12425–12430

    Article  PubMed Central  PubMed  Google Scholar 

  37. Sugano G, Bernard-Pierrot I, Lae M et al (2011) Milk fat globule–epidermal growth factor–factor VIII (MFGE8)/lactadherin promotes bladder tumor development. Oncogene 30:642–653

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine II, Faculty of Medicine, Shimane University, 89-1, Enya-cho, Izumo, Shimane, Japan

    Shunji Ishihara MD, PhD, Ryusaku Kusunoki MD, PhD & Yoshikazu Kinoshita MD, PhD

Authors
  1. Shunji Ishihara MD, PhD
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  2. Ryusaku Kusunoki MD, PhD
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  3. Yoshikazu Kinoshita MD, PhD
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Corresponding author

Correspondence to Shunji Ishihara MD, PhD .

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Editors and Affiliations

  1. Center for Translational Research, The Feinstein Inst. for Medical Research, Manhasset, New York, USA

    Ping Wang

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Ishihara, S., Kusunoki, R., Kinoshita, Y. (2014). Anti-Inflammatory Role of MFG-E8 in the Intestinal Tract. In: Wang, P. (eds) MFG-E8 and Inflammation. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-8765-9_8

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