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.
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Authors | Hidefumi Komura, Michael Miksa, Rongqian Wu, Sanna M Goyert, Ping Wang |
Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 182
Issue 1
Pg. 581-7
(Jan 01 2009)
ISSN: 1550-6606 [Electronic] United States |
PMID | 19109191
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Antigens, Surface
- Lipopolysaccharide Receptors
- Lipopolysaccharides
- Mfge8 protein, mouse
- Milk Proteins
- RNA, Messenger
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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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