Fractalkine-Induced MFG-E8 Leads to Enhanced Apoptotic Cell Clearance by Macrophages
Open accessAbstract
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 CX(3)C-chemokine fractalkine (CX(3)CL1) promotes apoptotic cell clearance through the induction of MFG-E8 in peritoneal macrophages. Cultured rat peritoneal macrophages (pMphi) and RAW264.7 macrophages were stimulated with LPS and CX(3)CL1. 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 CX(3)CL1 induced MFG-E8 expression in both nonstimulated and LPS-stimulated pMphi, without affecting TNF-alpha and IL-6 release. Anti-MFG-E8 blocking antibodies completely abrogated the prophagocytic effect of CX(3)CL1. Twenty hours after the induction of sepsis in rats via CLP, plasma CX(3)CL1 levels as well as MFG-E8 production in peritoneal macrophages decreased by 21% and 56%, respectively. Administration of CX(3)CL1 on the other hand induced MFG-E8 and prevented tissue injury. We conclude that CX(3)CL1 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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CD31 and CD47 are examples of don't-eat-me signals, although how cell death negates them remains unexplored.
“Examples of such signals are CD31 117 and CD47 118, although how these molecules are negated by cell death remains unexplored.”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [117]
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References 40 · Cited by 118
Research works printed but not linked: 1
- Meucci O, Fatatis A, Simen AA, Bushell TJ, Gray PW, Miller RJ. (1998) Chemokines regulate hip- pocampal neuronal signaling and gp120 neuro- toxicity. Proc. Natl. Acad. Sci. U. S. A. 95:14500-5.
- Authors
- Miksa, M., Amin, D., Wu, R., Dong, W., Ravikumar, T. S., & Wang, P.
- Affiliations
- Feinstein Institute for Medical Research (US)
- North Shore University Hospital (US)
- Corresponding author
- Wang, Ping
- Venue
- Molecular Medicine
- Published
- 2007-11
- Volume
- 13
- Issue
- 11-12
- Pages
- 553-560
- ISSN
- 1076-1551 (ISSN-L)
- 1528-3658
- PMC
- PMC1936982
- OpenAlex
- W2415209394
- Cited by
- 118
- References
- 40
- Citations by year
- 2025: 8 · 2024: 5 · 2023: 5 · 2022: 7 · 2021: 8 · 2020: 5 · 2019: 4 · 2018: 1 · 2017: 7 · 2016: 9 · 2015: 7 · 2014: 9 · 2013: 11 · 2012: 6
- FWCI
- 1.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (HL076179)
- National Heart, Lung, and Blood Institute (R01HL076179)
- National Institute of General Medical Sciences (R01GM057468)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- fractalkine, MFG-E8, efferocytosis, phagocytosis, peritoneal macrophages, sepsis, lipopolysaccharide, opsonins, dendritic cell-derived exosomes, cecal ligation and puncture, tissue damage
- MeSH terms
- Animals, Cell Line, Enzyme-Linked Immunosorbent Assay, Male, Milk Proteins, Phagocytosis, Recombinant Proteins, Blotting, Western, Rats, Sprague-Dawley, Apoptosis, Macrophages, Peritoneal, Rats, Chemokine CX3CL1
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