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Role of distinct fibroblast lineages and immune cells in dermal repair following UV radiation induced tissue damage

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Emanuel Rognoni, Georgina Goss, Toru Hiratsuka, Kalle H Sipilä, Thomas Kirk, Katharina I Kober, Prudence PokWai Lui, Victoria Sk Tsang, Nathan J Hawkshaw, Suzanne M Pilkington, Inchul Cho, Niwa Ali, Lesley E Rhodes, Fiona M Watt

Original languageEnglish
Article numbere71052
JournaleLife
Volume10
Early online date23 Dec 2021
DOIs
E-pub ahead of print23 Dec 2021
PublishedDec 2021

Bibliographical note

Funding Information: F.M.W. acknowledges financial support from the UK Medical Research Council (MR/PO18823/1), the Wellcome Trust (206439/Z/17/Z) and Cancer Research UK (C219/A23522). E.R. is the recipient of a European Molecular Biology Organization (EMBO) long-term fellowship [ALTF594-2014] and advanced fellowship [ALTF523-2017] and T.K. received funding from the Medical College?of?Saint?Bartholomew’s? Hospital Trust. This work was funded by grants to F.M.W. The human study was funded by the Wellcome Trust (grant WT94028, L.E.R.) and the NIHR Manchester Biomedical Research Centre (N.J.H, L.E.R.). Funding Information: F.M.W. acknowledges financial support from the UK Medical Research Council (MR/PO18823/1), the Wellcome Trust (206439/Z/17/Z) and Cancer Research UK (C219/A23522). E.R. is the recipient of a European Molecular Biology Organization (EMBO) long-term fellowship [ALTF594-2014] and advanced fellowship [ALTF523-2017] and T.K. received funding from the Medical College of Saint Bartholomew?s Hospital Trust. This work was funded by grants to F.M.W. The human study was funded by the Wellcome Trust (grant WT94028, L.E.R.) and the NIHR Manchester Biomedical Research Centre (N.J.H, L.E.R.). The authors acknowledge the use of core facilities provided by financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre 23 award to Guy?s & St Thomas? NHS Foundation Trust in partnership with King?s College London and King?s College Hospital NHS Foundation Trust. Publisher Copyright: © 2021, eLife Sciences Publications Ltd. All rights reserved.

King's Authors

Abstract

Solar ultraviolet radiation (UVR) is a major source of skin damage, resulting in inflammation, premature ageing and cancer. While several UVR-induced changes, including extracellular matrix reorganisation and epidermal DNA damage, have been documented, the role of different fibroblast lineages and their communication with immune cells has not been explored. We show that acute and chronic UVR exposure led to selective loss of fibroblasts from the upper dermis in human and mouse skin. Lineage tracing and in vivo live imaging revealed that repair following acute UVR is predominantly mediated by papillary fibroblast proliferation and fibroblast reorganisation occurs with minimal migration. In contrast, chronic UVR exposure led to a permanent loss of papillary fibroblasts, with expansion of fibroblast membrane protrusions partially compensating for the reduction in cell number. Although UVR strongly activated Wnt-signalling in skin, stimulation of fibroblast proliferation by epidermal b-catenin stabilisation did not enhance papillary dermis repair. Acute UVR triggered an infiltrate of neutrophils and T cell subpopulations and increased pro-inflammatory prostaglandin signalling in skin. Depletion of CD4 and CD8 positive cells resulted in increased papillary fibroblast depletion, which correlated with an increase in DNA damage, pro-inflammatory prostaglandins and reduction in fibroblast proliferation. Conversely, topical COX-2 inhibition prevented fibroblast depletion and neutrophil infiltration after UVR. We conclude that loss of papillary fibroblasts is primarily induced by a deregulated inflammatory response, with infiltrating T cells supporting fibroblast survival upon UVR-induced environmental stress.

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