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Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin

Nature Immunology volume 13, pages 744–752 (2012)Cite this article

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Abstract

Langerhans cells (LCs) are epidermal dendritic cells with incompletely understood origins that associate with hair follicles for unknown reasons. Here we show that in response to external stress, mouse hair follicles recruited Gr-1hi monocyte-derived precursors of LCs whose epidermal entry was dependent on the chemokine receptors CCR2 and CCR6, whereas the chemokine receptor CCR8 inhibited the recruitment of LCs. Distinct hair-follicle regions had differences in their expression of ligands for CCR2 and CCR6. The isthmus expressed the chemokine CCL2; the infundibulum expressed the chemokine CCL20; and keratinocytes in the bulge produced the chemokine CCL8, which is the ligand for CCR8. Thus, distinct hair-follicle keratinocyte subpopulations promoted or inhibited repopulation with LCs via differences in chemokine production, a feature also noted in humans. Pre-LCs failed to enter hairless skin in mice or humans, which establishes hair follicles as portals for LCs.

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Figure 1: MHCII+Lang− cells of myeloid phenotype infiltrate epidermis depleted of LCs.
Figure 2: LysM-expressing precursors give rise to a subset of LCs.
Figure 3: Dependence of LCs and pre-LCs on chemokine receptors.
Figure 4: Pre-LCs repopulate the epidermis via hair follicles.
Figure 5: Hair-follicle keratinocyte subsets are the main source of chemokines that regulate the entry of LCs.
Figure 6: S1P1 expression identifies CCL8-producing suprabasal hair-follicle bulge cells.
Figure 7: Pre-LCs fail to populate hairless epidermis.
Figure 8: Chemokine expression in human hair follicles and LCs in hairless skin.

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Acknowledgements

We thank K. Eguchi and H. Ito for assistance, and M. Kajimura for assistance with multiphoton microscopy. Supported by the Japan Society for the Promotion of Science (K.N. and M.A.), The Kanae Foundation for the Promotion of Medical Science, and Japaneses Dermatological Association (K.N.), The Netherlands Organization for Scientific Research (B.E.C.) and the Intramural Research Program of the Center for Cancer Research of the National Cancer Institute (M.C.U.).

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Authors and Affiliations

  1. Department of Dermatology, Keio University School of Medicine, Tokyo, Japan

    Keisuke Nagao, Tetsuro Kobayashi, Manabu Ohyama, Takeya Adachi, Daniela Y Kitashima, Akiharu Kubo & Masayuki Amagai

  2. Laboratory for Immune Cell System, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan

    Kazuyo Moro

  3. Department of Preventive Medicine, University of Tokyo, Tokyo, Japan

    Satoshi Ueha & Kouji Matsushima

  4. Department of Orthopedics, Keio University School of Medicine, Tokyo, Japan

    Keisuke Horiuchi

  5. Center for Integrated Medical Research, Keio University School of Medicine, Tokyo, Japan

    Keisuke Horiuchi & Akiharu Kubo

  6. Department of Dermatology, Kyoto University Faculty of Medicine, Kyoto, Japan

    Hideaki Tanizaki & Kenji Kabashima

  7. Dermatology Branch, Center for Cancer Research, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA

    Young-hun Cho & Mark C Udey

  8. Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands

    Björn E Clausen

  9. Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan

    Makoto Suematsu

  10. Japan Science and Technology Agency, Exploratory Research for Advanced Technology, Suematsu Gas Biology Project, Tokyo, Japan

    Makoto Suematsu

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

    Glaucia C Furtado & Sergio A Lira

  12. Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA

    Joshua M Farber

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Contributions

K.N. conceived of and designed all experiments; K.N. and T.K. did experiments, with the assistance of K.Mo., T.A., D.Y.M., S.U., K.H., M.O., A.K. and Y.C.; B.E.C. provided Langerin-DTR mice; K.Ma. provided bone marrow from mice deficient in CCR1, CCR2 or CCR5 and Cx3cr1gfp/gfp mice; G.C.F. and S.A.L. provided bone marrow from CCR8-deficient mice; J.M.F. provided bone marrow from CCR6-deficient mice; H.T., K.K. and M.S. assisted with multiphoton intravital microscopy; K.Mo. assisted with the sorting of hair-follicle keratinocytes; M.C.U. and M.A. interpreted data and guided the project; and K.N. and M.C.U. wrote the manuscript.

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Correspondence to Keisuke Nagao.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 and Table 1 (PDF 556 kb)

Supplementary Video 1

Multi-photon microscopy of DC recruitment to skin in vivo. (MOV 12159 kb)

Supplementary Video 2

Multi-photon microscopy of pre-LCs repopulation via HFs. (MOV 52721 kb)

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Nagao, K., Kobayashi, T., Moro, K. et al. Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin. Nat Immunol 13, 744–752 (2012). https://doi.org/10.1038/ni.2353

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