Epidermal Notch1 recruits RORγ(+) group 3 innate lymphoid cells to orchestrate normal skin repair

Zhi Li; Tom Hodgkinson; Elizabeth J Gothard; Soulmaz Boroumand; Rebecca Lamb; Ian Cummins; Priyanka Narang; Amy Sawtell; Jenny Coles; German Leonov; Andrea Reboldi; Christopher D Buckley; Tom Cupedo; Christian Siebel; Ardeshir Bayat; Mark C Coles; Carrie A Ambler

doi:10.1038/ncomms11394

Epidermal Notch1 recruits RORγ(+) group 3 innate lymphoid cells to orchestrate normal skin repair

Nat Commun. 2016 Apr 21:7:11394. doi: 10.1038/ncomms11394.

Authors

Zhi Li^{1

2}, Tom Hodgkinson³, Elizabeth J Gothard², Soulmaz Boroumand¹, Rebecca Lamb¹, Ian Cummins¹, Priyanka Narang², Amy Sawtell², Jenny Coles², German Leonov², Andrea Reboldi⁴, Christopher D Buckley⁵, Tom Cupedo⁶, Christian Siebel⁷, Ardeshir Bayat³, Mark C Coles², Carrie A Ambler¹

Affiliations

¹ School of Biological and Biomedical Sciences, Biophysical Sciences Institute, Durham University, Durham DH1 3LE, UK.
² Centre for Immunology and Infection, Department of Biology and Hull York Medical School, York YO10 5DD, UK.
³ Institute for Inflammation and Repair, University of Manchester, Manchester M1 7DN, UK.
⁴ Department of Microbiology and Immunology, University of California, San Francisco, California 94143, USA.
⁵ MRC Centre for Immune Regulation, University of Birmingham, Birmingham B15 2TT, UK.
⁶ Department of Hematology, Erasmus University Medical Center, Rotterdam 3015CN, Netherlands.
⁷ Department of Molecular Biology, Division of Research, Genentech Inc, South San Francisco, California 94080, USA.

Abstract

Notch has a well-defined role in controlling cell fate decisions in the embryo and the adult epidermis and immune systems, yet emerging evidence suggests Notch also directs non-cell-autonomous signalling in adult tissues. Here, we show that Notch1 works as a damage response signal. Epidermal Notch induces recruitment of immune cell subsets including RORγ(+) ILC3s into wounded dermis; RORγ(+) ILC3s are potent sources of IL17F in wounds and control immunological and epidermal cell responses. Mice deficient for RORγ(+) ILC3s heal wounds poorly resulting from delayed epidermal proliferation and macrophage recruitment in a CCL3-dependent process. Notch1 upregulates TNFα and the ILC3 recruitment chemokines CCL20 and CXCL13. TNFα, as a Notch1 effector, directs ILC3 localization and rates of wound healing. Altogether these findings suggest that Notch is a key stress/injury signal in skin epithelium driving innate immune cell recruitment and normal skin tissue repair.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Movement / immunology
Chemokine CCL20 / genetics
Chemokine CCL20 / immunology
Chemokine CXCL13 / genetics
Chemokine CXCL13 / immunology
Epidermis / immunology*
Epidermis / injuries
Female
Gene Expression Regulation
Immunity, Innate*
Interleukin-17 / genetics
Interleukin-17 / immunology
Lymphocyte Subsets / metabolism*
Male
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Knockout
Nuclear Receptor Subfamily 1, Group F, Member 3 / deficiency
Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology*
Receptor, Notch1 / genetics
Receptor, Notch1 / immunology*
Signal Transduction / immunology
Tumor Necrosis Factor-alpha / genetics
Tumor Necrosis Factor-alpha / immunology
Wound Healing / genetics
Wound Healing / immunology
Wounds, Penetrating / genetics
Wounds, Penetrating / immunology*
Wounds, Penetrating / pathology

Substances

CCL20 protein, mouse
Chemokine CCL20
Chemokine CXCL13
Cxcl13 protein, mouse
Interleukin-17
Notch1 protein, mouse
Nuclear Receptor Subfamily 1, Group F, Member 3
Receptor, Notch1
Rorc protein, mouse
Tumor Necrosis Factor-alpha

Abstract

Publication types

MeSH terms

Substances

Grants and funding