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* Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center and The Feinstein Institute for Medical Research, Manhasset, NY 11030; and
Department of Microbiology and Immunology, The Sophie Davis School of Biomedical Education, The City University of New York, New York, NY 10031
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants R01 GM057468, R01 GM053008, and R01 AG028352 (to P.W.).
2 Address correspondence and reprint requests to Dr. Ping Wang, Laboratory of Surgical Research, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030. E-mail address: pwang{at}nshs.edu
3 Abbreviations used in this paper: SIRS, systemic inflammatory response syndrome; MFG-E8, milk fat globule EGF-factor VIII; EGF, epidermal growth factor; CLP, cecal ligation and puncture; WT, wild type; BW, body weight; MFI, mean fluorescence intensity; PI, propidium iodine.
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