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

  1. Emanuel Rognoni  Is a corresponding author
  2. Georgina Goss
  3. Toru Hiratsuka
  4. Kalle H Sipilä
  5. Thomas Kirk
  6. Katharina I Kober
  7. Prudence PokWai Lui
  8. Victoria SK Tsang
  9. Nathan J Hawkshaw
  10. Suzanne M Pilkington
  11. Inchul Cho
  12. Niwa Ali
  13. Lesley E Rhodes
  14. Fiona M Watt  Is a corresponding author
  1. Queen Mary University of London, United Kingdom
  2. King's College London, United Kingdom
  3. German Cancer Research Center (DKFZ), Germany
  4. The University of Manchester and Salford Royal NHS Foundation Trust, United Kingdom

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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source Data files containing the numerical data used to generate the figures have been provided for all figures.

The following previously published data sets were used

Article and author information

Author details

  1. Emanuel Rognoni

    Centre for Endocrinology, Queen Mary University of London, London, United Kingdom
    For correspondence
    e.rognoni@qmul.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6050-2860
  2. Georgina Goss

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  3. Toru Hiratsuka

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5359-2690
  4. Kalle H Sipilä

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  5. Thomas Kirk

    Centre for Endocrinology, Queen Mary University of London, London, United Kingdom
    Competing interests
    No competing interests declared.
  6. Katharina I Kober

    Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8076-3379
  7. Prudence PokWai Lui

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  8. Victoria SK Tsang

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  9. Nathan J Hawkshaw

    Division of Musculoskeletal and Dermatological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester, United Kingdom
    Competing interests
    No competing interests declared.
  10. Suzanne M Pilkington

    Division of Musculoskeletal and Dermatological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester, United Kingdom
    Competing interests
    No competing interests declared.
  11. Inchul Cho

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5527-0962
  12. Niwa Ali

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4473-8747
  13. Lesley E Rhodes

    Division of Musculoskeletal and Dermatological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9107-6654
  14. Fiona M Watt

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    For correspondence
    fiona.watt@kcl.ac.uk
    Competing interests
    Fiona M Watt, FW is on secondment as Executive Chair of the Medical Research Council. The author has no other competing interests to declare..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9151-5154

Funding

Cancer Research UK (C219/A23522)

  • Fiona M Watt

Medical Research Council (MR/PO18823/1)

  • Fiona M Watt

Wellcome Trust (206439/Z/17/Z)

  • Fiona M Watt

Wellcome Trust (WT94028)

  • Lesley E Rhodes

NIHR Greater Manchester Patient Safety Translational Research Centre

  • Nathan J Hawkshaw
  • Lesley E Rhodes

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were subject to local ethical approval and performed under the terms of a UKgovernment Home Office license (PPL 70/8474 or PP0313918).

Human subjects: Ethical approval was granted by the Greater Manchester North NHS research ethics committee (ref:11/NW/0567) for the studies presented in Figure 1 and Figure 6. Details of the time course analysis of UVRchallenged human skin have been reported previously (Hawkshaw NJ et al. 2020). All volunteers provided written informed consent in accordance with the Declaration of Helsinki principles.

Copyright

© 2021, Rognoni et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,160
    views
  • 565
    downloads
  • 19
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Emanuel Rognoni
  2. Georgina Goss
  3. Toru Hiratsuka
  4. Kalle H Sipilä
  5. Thomas Kirk
  6. Katharina I Kober
  7. Prudence PokWai Lui
  8. Victoria SK Tsang
  9. Nathan J Hawkshaw
  10. Suzanne M Pilkington
  11. Inchul Cho
  12. Niwa Ali
  13. Lesley E Rhodes
  14. Fiona M Watt
(2021)
Role of distinct fibroblast lineages and immune cells in dermal repair following UV radiation induced tissue damage
eLife 10:e71052.
https://doi.org/10.7554/eLife.71052

Share this article

https://doi.org/10.7554/eLife.71052

Further reading

    1. Cell Biology
    Tomoharu Kanie, Roy Ng ... Peter K Jackson
    Research Article

    The primary cilium is a microtubule-based organelle that cycles through assembly and disassembly. In many cell types, formation of the cilium is initiated by recruitment of ciliary vesicles to the distal appendage of the mother centriole. However, the distal appendage mechanism that directly captures ciliary vesicles is yet to be identified. In an accompanying paper, we show that the distal appendage protein, CEP89, is important for the ciliary vesicle recruitment, but not for other steps of cilium formation (Tomoharu Kanie, Love, Fisher, Gustavsson, & Jackson, 2023). The lack of a membrane binding motif in CEP89 suggests that it may indirectly recruit ciliary vesicles via another binding partner. Here, we identify Neuronal Calcium Sensor-1 (NCS1) as a stoichiometric interactor of CEP89. NCS1 localizes to the position between CEP89 and a ciliary vesicle marker, RAB34, at the distal appendage. This localization was completely abolished in CEP89 knockouts, suggesting that CEP89 recruits NCS1 to the distal appendage. Similarly to CEP89 knockouts, ciliary vesicle recruitment as well as subsequent cilium formation was perturbed in NCS1 knockout cells. The ability of NCS1 to recruit the ciliary vesicle is dependent on its myristoylation motif and NCS1 knockout cells expressing a myristoylation defective mutant failed to rescue the vesicle recruitment defect despite localizing properly to the centriole. In sum, our analysis reveals the first known mechanism for how the distal appendage recruits the ciliary vesicles.

    1. Cell Biology
    Ling Cheng, Ian Meliala ... Mikael Björklund
    Research Article

    Mitochondrial dysfunction is involved in numerous diseases and the aging process. The integrated stress response (ISR) serves as a critical adaptation mechanism to a variety of stresses, including those originating from mitochondria. By utilizing mass spectrometry-based cellular thermal shift assay (MS-CETSA), we uncovered that phosphatidylethanolamine-binding protein 1 (PEBP1), also known as Raf kinase inhibitory protein (RKIP), is thermally stabilized by stresses which induce mitochondrial ISR. Depletion of PEBP1 impaired mitochondrial ISR activation by reducing eukaryotic translation initiation factor 2α (eIF2α) phosphorylation and subsequent ISR gene expression, which was independent of PEBP1’s role in inhibiting the RAF/MEK/ERK pathway. Consistently, overexpression of PEBP1 potentiated ISR activation by heme-regulated inhibitor (HRI) kinase, the principal eIF2α kinase in the mitochondrial ISR pathway. Real-time interaction analysis using luminescence complementation in live cells revealed an interaction between PEBP1 and eIF2α, which was disrupted by eIF2α S51 phosphorylation. These findings suggest a role for PEBP1 in amplifying mitochondrial stress signals, thereby facilitating an effective cellular response to mitochondrial dysfunction. Therefore, PEBP1 may be a potential therapeutic target for diseases associated with mitochondrial dysfunction.