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Apoptotic neutrophils and T cells sequester chemokines during immune response resolution through modulation of CCR5 expression

Nature Immunology volume 7, pages 1209–1216 (2006)Cite this article

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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Figure 1: Increased CCL3 and CCL5 in peritoneal exudates from Ccr5−/− mice during the resolution of peritonitis.
Figure 2: Ccr5−/− macrophages engulf apoptotic PMNs more efficiently than do wild-type macrophages.
Figure 3: Ccr5−/− macrophages are more mature than wild-type macrophages.
Figure 4: CCR5 mediates chemokine scavenging by apoptotic PMNs.
Figure 5: Regulation of CCR5 expression on late apoptotic human PMNs.
Figure 6: Apoptotic activated peripheral blood T cells have high expression of CCR5.
Figure 7: Late apoptotic T cells have high expression of CCR5.
Figure 8: CCR5 on apoptotic cells has characteristics different from those of CCR5 on live cells.

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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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Authors and Affiliations

  1. Department of Anesthesiology, Center for Experimental Therapeutics and Reperfusion Injury, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Amiram Ariel, Gabrielle Fredman, Yee-Ping Sun & Charles N Serhan

  2. Department of Periodontology and Oral Biology, Goldman School of Dental Medicine, Boston University, Boston, 02118, Massachusetts, USA

    Alpdogan Kantarci & Thomas E Van Dyke

  3. Division of Rheumatology, Center for Immunology and Inflammatory Diseases, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Charlestown, 02129, Massachusetts, USA

    Andrew D Luster

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Contributions

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.

Corresponding author

Correspondence to Charles N Serhan.

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Competing interests

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)

Supplementary Methods (PDF 68 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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