Epidermal Notch1 recruits RORγ(+) group 3 innate lymphoid cells to orchestrate normal skin repair.
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.
School of Biological and Biomedical Sciences, Biophysical Sciences Institute, Durham University, Durham DH1 3LE, UK.|Centre for Immunology and Infection, Department of Biology and Hull York Medical School, York YO10 5DD, UK.
Zhi
Z
Li
Institute for Inflammation and Repair, University of Manchester, Manchester M1 7DN, UK.
Tom
T
Hodgkinson
Centre for Immunology and Infection, Department of Biology and Hull York Medical School, York YO10 5DD, UK.
Elizabeth J
EJ
Gothard
School of Biological and Biomedical Sciences, Biophysical Sciences Institute, Durham University, Durham DH1 3LE, UK.
Soulmaz
S
Boroumand
School of Biological and Biomedical Sciences, Biophysical Sciences Institute, Durham University, Durham DH1 3LE, UK.
Rebecca
R
Lamb
School of Biological and Biomedical Sciences, Biophysical Sciences Institute, Durham University, Durham DH1 3LE, UK.
Ian
I
Cummins
Centre for Immunology and Infection, Department of Biology and Hull York Medical School, York YO10 5DD, UK.
Priyanka
P
Narang
Centre for Immunology and Infection, Department of Biology and Hull York Medical School, York YO10 5DD, UK.
Amy
A
Sawtell
Centre for Immunology and Infection, Department of Biology and Hull York Medical School, York YO10 5DD, UK.
Jenny
J
Coles
Centre for Immunology and Infection, Department of Biology and Hull York Medical School, York YO10 5DD, UK.
German
http://orcid.org/0000-0002-6763-5903
G
Leonov
Department of Microbiology and Immunology, University of California, San Francisco, California 94143, USA.
Andrea
A
Reboldi
MRC Centre for Immune Regulation, University of Birmingham, Birmingham B15 2TT, UK.
Christopher D
CD
Buckley
Department of Hematology, Erasmus University Medical Center, Rotterdam 3015CN, Netherlands.
Tom
T
Cupedo
Department of Molecular Biology, Division of Research, Genentech Inc, South San Francisco, California 94080, USA.
Christian
C
Siebel
Institute for Inflammation and Repair, University of Manchester, Manchester M1 7DN, UK.
Ardeshir
A
Bayat
Centre for Immunology and Infection, Department of Biology and Hull York Medical School, York YO10 5DD, UK.
Mark C
MC
Coles
School of Biological and Biomedical Sciences, Biophysical Sciences Institute, Durham University, Durham DH1 3LE, UK.
Carrie A
http://orcid.org/0000-0002-2697-7376
CA
Ambler
D000818:Animals; D002465:Cell Movement / Q000276:immunology; D054418:Chemokine CCL20 / Q000235:genetics / Q000276:immunology; D054382:Chemokine CXCL13 / Q000235:genetics / Q000276:immunology; D004817:Epidermis / Q000276:immunology* / Q000293:injuries; D005260:Female; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D016131:Lymphocyte Subsets / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051881:Receptor, Notch1 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D014945:Wound Healing / Q000235:genetics / Q000276:immunology; D014950:Wounds, Penetrating / Q000235:genetics / Q000276:immunology* / Q000473:pathology
C493447:CCL20 protein, mouse; D054418:Chemokine CCL20; D054382:Chemokine CXCL13; C486386:Cxcl13 protein, mouse; D020381:Interleukin-17; C497762:Notch1 protein, mouse; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D051881:Receptor, Notch1; C539901:Rorc protein, mouse; D014409:Tumor Necrosis Factor-alpha