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Mouse CCL8, a CCR8 agonist, promotes atopic dermatitis by recruiting IL-5+ TH2 cells

Nature Immunology volume 12, pages 167–177 (2011)Cite this article

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Abstract

Mouse CCL8 is a CC chemokine of the monocyte chemoattractant protein (MCP) family whose biological activity and receptor usage have remained elusive. Here we show that CCL8 is highly expressed in the skin, where it serves as an agonist for the chemokine receptor CCR8 but not for CCR2. This distinguishes CCL8 from all other MCP chemokines. CCL8 responsiveness defined a population of highly differentiated, CCR8-expressing inflammatory T helper type 2 (TH2) cells enriched for interleukin (IL)-5. Ccr8- and Ccl8-deficient mice had markedly less eosinophilic inflammation than wild-type or Ccr4-deficient mice in a model of chronic atopic dermatitis. Adoptive transfer studies established CCR8 as a key regulator of TH2 cell recruitment into allergen-inflamed skin. In humans, CCR8 expression also defined an IL-5–enriched TH2 cell subset. The CCL8-CCR8 chemokine axis is therefore a crucial regulator of TH2 cell homing that drives IL-5–mediated chronic allergic inflammation.

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Figure 1: Mouse CCL8 RNA and protein are detected in normal mouse skin.
Figure 2: Mouse CCL8 induces migration and calcium flux in TH2-R2A cells.
Figure 3: CCR8 is required for mouse CCL8-induced TH2-R2A cell migration.
Figure 4: Mouse CCL8 is a specific agonist of mouse and human CCR8.
Figure 5: Ccr8−/− and Ccl8−/−Ccl12−/− mice have decreased skin inflammation in a model of chronic atopic dermatitis.
Figure 6: Ccr8−/− mice have decreased production of IL-5, IL-25 and eosinophil-active chemokines in allergen-sensitized skin.
Figure 7: Competitive in vivo homing of adoptively transferred OVA-specific wild-type and Ccr8−/− TH2 and TH1 cells in OVA-sensitized mice.
Figure 8: Mouse CCL8–responsive TH2-R2A cells are enriched for IL-5, IL-25R, TNF and OX40.

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Acknowledgements

This work is funded by US National Institutes of Health grants K08-AI556663 and P30AR042689 (Harvard Skin Disease Research Center Pilot & Feasibility Study) to S.A.I. and R37-AI040618 to A.D.L., and the Infectious Diseases Society of America Young Investigator Award to S.A.I. The authors thank P. Murphy (National Institutes of Health) for 4DE4 cells, J. Pease (Imperial College London) for human CCR8 receptor transfectants, P. Shrikant (Roswell Park Cancer Institute) for transgenic Thy1.1 OTII mice, L. Lefrancois (University of Connecticut School of Medicine) for transgenic Thy1.2 OTII mice, C. Sanderson (National Institute for Medical Research, London) for Il5–transgenic mice, S. Thomas for assistance with calcium flux studies and T. Means for assistance with design and validation of QPCR primers.

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Authors and Affiliations

  1. Division of Rheumatology, Center for Immunology and Inflammatory Diseases, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Sabina A Islam, Daniel S Chang, Richard A Colvin, Mike H Byrne & Andrew D Luster

  2. Department of Infection, Immunity and Biochemistry, Cardiff University, Cardiff, UK

    Michelle L McCully & Bernhard Moser

  3. The Immunology Institute, Mount Sinai School of Medicine, New York, New York, USA

    Sergio A Lira

  4. Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California, USA

    Israel F Charo

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Contributions

A.D.L. screened the EST database to identify mouse Ccl8, designed the construct to express functional recombinant mouse CCL8 protein, conducted the RNA blot analysis, designed experiments and wrote the paper. D.S.C. did mouse experiments, immunohistochemistry and QPCR of skin RNA preps. R.A.C. helped devise a strategy to clone Ccr8 and helped generate Ccr2 transient transfectants. M.H.B. helped clone Ccr8. M.L.M. and B.M. generated and provided the biotinylated monoclonal antibody to human CCR8. S.A.L. provided the Ccr8−/− mice, and I.F.C. provided the Ccl8−/−Ccl12−/− and Ccl12−/− mice. S.A.I. carried out all other in vitro and in vivo experiments, designed research, analyzed data and wrote the paper.

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Correspondence to Andrew D Luster.

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Islam, S., Chang, D., Colvin, R. et al. Mouse CCL8, a CCR8 agonist, promotes atopic dermatitis by recruiting IL-5+ TH2 cells. Nat Immunol 12, 167–177 (2011). https://doi.org/10.1038/ni.1984

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