Impaired Epidermal to Dendritic T Cell Signaling Slows Wound Repair in Aged Skin
Open accessAbstract
Aged skin heals wounds poorly, increasing susceptibility to infections. Restoring homeostasis after wounding requires the coordinated actions of epidermal and immune cells. Here we find that both intrinsic defects and communication with immune cells are impaired in aged keratinocytes, diminishing their efficiency in restoring the skin barrier after wounding. At the wound-edge, aged keratinocytes display reduced proliferation and migration. They also exhibit a dampened ability to transcriptionally activate epithelial-immune crosstalk regulators, including a failure to properly activate/maintain dendritic epithelial T cells (DETCs), which promote re-epithelialization following injury. Probing mechanism, we find that aged keratinocytes near the wound edge don't efficiently upregulate Skints or activate STAT3. Notably, when epidermal Stat3, Skints, or DETCs are silenced in young skin, re-epithelialization following wounding is perturbed. These findings underscore epithelial-immune crosstalk perturbations in general, and Skints in particular, as critical mediators in the age-related decline in wound-repair.
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In animal models of IPF, bleomycin-induced injury and telomere deficiency drive fibroblasts and epithelial cells towards increased senescence, a feature also observed in lung tissue of IPF patients.
“In animal models of idiopathic pulmonary fibrosis (IPF), bleomycin-induced injury66 and telomere deficiency72 drive fibroblasts and epithelial cells towards increased levels of senescence, a feature also observed in the lung tissue of patients with IPF.”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [72]
The Results section on aged keratinocytes addresses wound repair in mouse skin, not senescence in pulmonary fibrosis. Searches for bleomycin, telomere deficiency, and lung fibrosis found no passage in our copy supporting the claim attributed to citation 72. (LLM, conf=0.77)
Experimental — accuracy not yet measuredOur results are conceptually consistent with previous reports of large transcriptional changes with age in some cell identities and more subtle changes in others.
“Our results are conceptually consistent with previous reports of large transcriptional changes with age in some cell identities and more subtle changes in others (Kowalczyk et al. 2015; Keyes et al. 2016; Davie et al. 2018; Keyes and Fuchs 2018).”
From Murine single-cell RNA-seq reveals cell-identity- and tissue-specific trajectories of aging (2019) · cites this paper as Keyes et al. 2016
We surprisingly found minor transcriptional differences between aged and young MuSCs at a given point in the activation process.
“We surprisingly found minor transcriptional differences between aged and young MuSCs at a given point in the activation process, consistent with previous reports (Cosgrove et al., 2014; Keyes et al., 2016; Sousa-Victor et al., 2014).”
From Aging induces aberrant state transition kinetics in murine muscle stem cells (2020) · cites this paper as Keyes et al., 2016
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“Wounds were measured 3, 4, and 5 days post-wounding, a time span that was previously shown to have the highest re-epithelialization activity (Keyes et al., 2016) (Figure 5C).”
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- Authors
- Keyes, B. E., Liu, S., Asare, A., Naik, S., Levorse, J., Polak, L., Lu, C. P., Nikolova, M., Pasolli, H. A., & Fuchs, E.
- Affiliations
- Rockefeller University (US)
- Corresponding author
- Fuchs, Elaine
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 167
- Issue
- 5
- Pages
- 1323-1338.e14
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5364946
- OpenAlex
- W2550080559
- Cited by
- 266
- References
- 52
- Citations by year
- 2026: 25 · 2025: 19 · 2024: 27 · 2023: 28 · 2022: 33 · 2021: 33 · 2020: 33 · 2019: 28 · 2018: 29 · 2017: 11
- FWCI
- 24.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH/NCI (CA009673-36A1)
- NIH (R01-AR050452)
- Ellison Foundation
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Keywords
- aged skin, wound healing, keratinocytes, epithelial-immune crosstalk, re-epithelialization, STAT3, skin barrier, aging, keratinocyte proliferation and migration
- MeSH terms
- Aging, Animals, Skin, Skin Physiological Phenomena, Wound Healing, Signal Transduction, Keratinocytes, Interleukin-6, Lymphocyte Subsets, Mice
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