Role of distinct fibroblast lineages and immune cells in dermal repair following UV radiation induced tissue damage
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.
-
Lef1 expression in fibroblasts maintains developmental potential in adult skin to regenerate woundsNCBI Gene Expression Omnibus, GSE153596.
Article and author information
Author details
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.
Reviewing Editor
- Edward E Morrisey, University of Pennsylvania, United States
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.
Version history
- Received: June 8, 2021
- Accepted: December 22, 2021
- Accepted Manuscript published: December 23, 2021 (version 1)
- Version of Record published: January 10, 2022 (version 2)
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
-
- 2,797
- views
-
- 515
- downloads
-
- 13
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
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)
Further reading
-
- Cell Biology
- Physics of Living Systems
An influx of water molecules can help immune cells called neutrophils to move to where they are needed in the body.
-
- Cell Biology
- Physics of Living Systems
While the involvement of actin polymerization in cell migration is well-established, much less is known about the role of transmembrane water flow in cell motility. Here, we investigate the role of water influx in a prototypical migrating cell, the neutrophil, which undergoes rapid, directed movement to sites of injury, and infection. Chemoattractant exposure both increases cell volume and potentiates migration, but the causal link between these processes are not known. We combine single-cell volume measurements and a genome-wide CRISPR screen to identify the regulators of chemoattractant-induced neutrophil swelling, including NHE1, AE2, PI3K-gamma, and CA2. Through NHE1 inhibition in primary human neutrophils, we show that cell swelling is both necessary and sufficient for the potentiation of migration following chemoattractant stimulation. Our data demonstrate that chemoattractant-driven cell swelling complements cytoskeletal rearrangements to enhance migration speed.