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

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

doi:10.1038/ncomms11394

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.

Highlights

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 directs non-cellautonomous signalling in adult tissues
ILC3s contribute to intestinal epithelial repair through IL22 upregulation[24], and through ILC3-mediated release of granulocyte macrophage colony stimulating factor (GM-CSF) controlling macrophage and dendritic cell responses to gut commensal microflora[25,26]
Using RORg þ -deficient mice, we present evidence that RORg þ ILC3s, in wounds, produce IL17F and CCL3 and have key roles the normal healing response; ILC3s control epidermal proliferation and macrophage entry into the dermis

Summary

Introduction

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 directs non-cellautonomous signalling in adult tissues. TNFa, as a Notch[1] effector, directs ILC3 localization and rates of wound healing These findings suggest that Notch is a key stress/injury signal in skin epithelium driving innate immune cell recruitment and normal skin tissue repair. Adaptive and innate immune cells regulate the skin wound healing process through production of cytokines, antimicrobial peptides and growth factors. Innate lymphoid cells (ILCs) are rare populations of lymphocytes that have key roles in secondary lymphoid tissue formation, homoeostasis and rapid production of cytokines in response to pathogen infection. Group 3 or ILC3s are characterized by the expression of RORg transcription factor and have key roles in the maintenance and repair of epithelial tissues. Controls dermal entry of inflammatory cell subsets, including NKp46low/–CD4 þ

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Conclusion