TY - JOUR
T1 - Fractalkine-induced MFG-E8 leads to enhanced apoptotic cell clearance by macrophages
AU - Miksa, Michael
AU - Amin, Dhruv
AU - Wu, Rongqian
AU - Dong, Weifeng
AU - Ravikumar, Thanjavur S.
AU - Wang, Ping
PY - 2007/11
Y1 - 2007/11
N2 - Clearance of apoptotic cells is crucial to maintain cellular function under normal and pathological conditions. We have recently shown that administration of immature dendritic cell-derived exosomes to septic animals promotes phagocytosis of apoptotic cells and improves survival by providing milk fat globule epidermal growth factor-factor VIII (MFG-E8). MFG-E8 acts as an opsonin for apoptotic cells to be engulfed by phagocytosis. In the present study we investigated whether the CX3C-chemokine fractalkine (CX 3CL1) promotes apoptotic cell clearance through the induction of MFG-E8 in peritoneal macrophages. Cultured rat peritoneal macrophages (pMφ) and RAW264.7 macrophages were stimulated with LPS and CX3CL1. MFG-E8 expression was assessed by Western blot, cytokine secretion was assessed by ELISA, and phagocytosis of apoptotic thymocytes was determined by microscopy. For in vivo studies, cecal ligation and puncture (CLP) was used to induce sepsis in rats and mice. LPS significantly decreased MFG-E8 levels and phagocytosis of apoptotic cells, whereas CX3CL1 induced MFG-E8 expression in both nonstimulated and LPS-stimulated pMφ, without affecting TNF-α and IL-6 release. Anti-MFG-E8 blocking antibodies completely abrogated the prophagocytic effect of CX3CL1. Twenty hours after the induction of sepsis in rats via CLP, plasma CX3CL1 levels as well as MFG-E8 production in peritoneal macrophages decreased by 21% and 56%, respectively. Administration of CX3CL1 on the other hand induced MFG-E8 and prevented tissue injury. We conclude that CX3CL1 induces MFG-E8 in vitro and in vivo and enhances clearance of apoptotic cells in an MFG-E8-dependent manner. These findings suggest a possible novel treatment for patients in sepsis.
AB - Clearance of apoptotic cells is crucial to maintain cellular function under normal and pathological conditions. We have recently shown that administration of immature dendritic cell-derived exosomes to septic animals promotes phagocytosis of apoptotic cells and improves survival by providing milk fat globule epidermal growth factor-factor VIII (MFG-E8). MFG-E8 acts as an opsonin for apoptotic cells to be engulfed by phagocytosis. In the present study we investigated whether the CX3C-chemokine fractalkine (CX 3CL1) promotes apoptotic cell clearance through the induction of MFG-E8 in peritoneal macrophages. Cultured rat peritoneal macrophages (pMφ) and RAW264.7 macrophages were stimulated with LPS and CX3CL1. MFG-E8 expression was assessed by Western blot, cytokine secretion was assessed by ELISA, and phagocytosis of apoptotic thymocytes was determined by microscopy. For in vivo studies, cecal ligation and puncture (CLP) was used to induce sepsis in rats and mice. LPS significantly decreased MFG-E8 levels and phagocytosis of apoptotic cells, whereas CX3CL1 induced MFG-E8 expression in both nonstimulated and LPS-stimulated pMφ, without affecting TNF-α and IL-6 release. Anti-MFG-E8 blocking antibodies completely abrogated the prophagocytic effect of CX3CL1. Twenty hours after the induction of sepsis in rats via CLP, plasma CX3CL1 levels as well as MFG-E8 production in peritoneal macrophages decreased by 21% and 56%, respectively. Administration of CX3CL1 on the other hand induced MFG-E8 and prevented tissue injury. We conclude that CX3CL1 induces MFG-E8 in vitro and in vivo and enhances clearance of apoptotic cells in an MFG-E8-dependent manner. These findings suggest a possible novel treatment for patients in sepsis.
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U2 - 10.2119/2007-00019.Miksa
DO - 10.2119/2007-00019.Miksa
M3 - Article
C2 - 17673941
AN - SCOPUS:36849080928
SN - 1076-1551
VL - 13
SP - 553
EP - 560
JO - Molecular Medicine
JF - Molecular Medicine
IS - 11-12
ER -