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

TY - JOUR

T1 - Role of distinct fibroblast lineages and immune cells in dermal repair following UV radiation induced tissue damage

AU - Rognoni, Emanuel

AU - Goss, Georgina

AU - Hiratsuka, Toru

AU - Sipilä, Kalle H

AU - Kirk, Thomas

AU - Kober, Katharina I

AU - Lui, Prudence PokWai

AU - Tsang, Victoria Sk

AU - Hawkshaw, Nathan J

AU - Pilkington, Suzanne M

AU - Cho, Inchul

AU - Ali, Niwa

AU - Rhodes, Lesley E

AU - Watt, Fiona M

N1 - 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.

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85122380516&partnerID=8YFLogxK

U2 - 10.7554/eLife.71052

DO - 10.7554/eLife.71052

M3 - Article

C2 - 34939928

SN - 2050-084X

VL - 10

JO - eLife

JF - eLife

M1 - e71052

ER -