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Milk fat globule epidermal growth factor-factor VIII is down-regulated in sepsis via the lipopolysaccharide-CD14 pathway.

Abstract
Phagocytosis prevents the release of potentially harmful or immunogenic materials from dying cells. Milk fat globule epidermal growth factor (EGF)-factor VIII (MFG-E8) mediates the clearance of apoptotic cells. We have previously shown that the administration of MFG-E8-rich exosomes from immature dendritic cells promotes the phagocytosis of apoptotic cells and improves survival in sepsis. Because endotoxin is elevated in polymicrobial sepsis, we hypothesized that down-regulation of MFG-E8 is mediated via the LPS-CD14 pathway, eventually leading to the accruement of apoptotic cells. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in CD14-deficient (CD14(-/-)), TLR4-mutated and wild-type (WT) mice. In addition, endotoxemia was elicited by i.p. injection of LPS. LPS was also neutralized by pretreating CLP-induced WT mice with polymyxin B. Splenic MFG-E8 expression, phagocytic activity, and apoptosis were assessed 5 and 20 h after CLP or 5 h after LPS administration. In septic WT mice, MFG-E8 mRNA and protein levels were suppressed by 49 and 33%, respectively. Endotoxemia reduced MFG-E8 mRNA expression in a dose dependent manner and the down-regulation of MFG-E8 mRNA expression in CLP-induced sepsis was attenuated by polymyxin B. This CLP-induced suppression was not observed in both CD14(-/-) and TLR4-mutated mice. CLP significantly decreased phagocytic activity of peritoneal macrophages in WT (by 30%), but not in CD14(-/-) mice. CLP also induced significant apoptosis in the spleen of WT (by 61%), but less in CD14(-/-) mice. Thus, MFG-E8 production is down-regulated in sepsis by LPS-CD14 dependent fashion, leading to a reduction of phagocytosis of apoptotic cells.
AuthorsHidefumi Komura, Michael Miksa, Rongqian Wu, Sanna M Goyert, Ping Wang
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 182 Issue 1 Pg. 581-7 (Jan 01 2009) ISSN: 1550-6606 [Electronic] United States
PMID19109191 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Antigens, Surface
  • Lipopolysaccharide Receptors
  • Lipopolysaccharides
  • Mfge8 protein, mouse
  • Milk Proteins
  • RNA, Messenger
Topics
  • Animals
  • Antigens, Surface (biosynthesis, genetics)
  • Apoptosis (immunology)
  • Dose-Response Relationship, Immunologic
  • Down-Regulation (genetics, immunology)
  • Endotoxemia (immunology, metabolism, pathology)
  • Lipopolysaccharide Receptors (genetics, physiology)
  • Lipopolysaccharides (physiology)
  • Male
  • Mice
  • Mice, Inbred C3H
  • Mice, Knockout
  • Mice, Mutant Strains
  • Milk Proteins (antagonists & inhibitors, biosynthesis, genetics)
  • Phagocytosis (genetics, immunology)
  • RNA, Messenger (antagonists & inhibitors, biosynthesis)
  • Signal Transduction (genetics, immunology)
  • Spleen (immunology, metabolism, pathology)

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