Abstract
During the resolution phase of inflammation, the 'corpses' of apoptotic leukocytes are gradually cleared by macrophages. Here we report that during the resolution of peritonitis, the CCR5 chemokine receptor ligands CCL3 and CCL5 persisted in CCR5-deficient mice. CCR5 expression on apoptotic neutrophils and activated apoptotic T cells sequestered and effectively cleared CCL3 and CCL5 from sites of inflammation. CCR5 expression on late apoptotic human polymorphonuclear cells was downregulated by proinflammatory stimuli, including tumor necrosis factor, and was upregulated by 'proresolution' lipid mediators, including lipoxin A4, resolvin E1 and protectin D1. Our results suggest that CCR5+ apoptotic leukocytes act as 'terminators' of chemokine signaling during the resolution of inflammation.
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Acknowledgements
We thank M.H. Small for assistance in manuscript preparation, and J. Deady for technical assistance. Supported by the US National Institutes of Health (GM38765, DK-074448 and P50-DE016191 to C.N.S., and DK-074449 to A.D.L.) and the Arthritis Foundation (A.A.).
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All authors were involved in experimental planning and data analysis and contributed to manuscript preparation. A.A. carried out FACS analysis, binding, chemotaxis, human cell isolation and cell culture; G.F. carried out experiments, FACS analysis, human cell isolation and culture; Y.-P.S. carried out peritonitis experiments and related analyses; A.K. and T.E.V.D. carried out Luminex analyses and related experimental design; A.D.L. carried out experiments with CCR5-deficient mice.
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C.N.S. is a consultant for the clinical development of lipoxin stable analogs with Berlex-Schering and for the development of Resolvin E1 with Resolvex Pharma.
Supplementary information
Supplementary Fig. 1
Ly-6G+F4/80+ in peritoneal exudates are PMN-macrophage conjugates. (PDF 170 kb)
Supplementary Fig. 2
Increased CCL4 binding to late apoptotic T cells. (PDF 219 kb)
Supplementary Fig. 3
Caspase inhibition abrogates apoptosis-induced modulation of CCL4 binding to late apoptotic T cells. (PDF 263 kb)
Supplementary Fig. 4
Scheme of the role of apoptotic leukocytes and pro-resolving lipid mediators in the resolution of inflammation. (PDF 412 kb)
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Ariel, A., Fredman, G., Sun, YP. et al. Apoptotic neutrophils and T cells sequester chemokines during immune response resolution through modulation of CCR5 expression. Nat Immunol 7, 1209–1216 (2006). https://doi.org/10.1038/ni1392
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DOI: https://doi.org/10.1038/ni1392
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