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

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.

A single dose of Ultraviolet-A induces proteome remodeling and senescence in primary human keratinocytes

Epidermal photoaging contributes to skin fragility over time and it is a risk factor for skin cancer. Photoaging has been associated for a long time with exposure to Ultraviolet-A (UVA) light, the predominant component of the solar ultraviolet radiation. While the cellular mechanisms underlying UVA-induced photoaging in the dermis have been well characterized, UVA’s action on the epidermis remains elusive. Here, proteomic analysis was conducted to derive the cellular responses induced by an environmentally relevant dose of UVA in primary human keratinocytes. We also investigated the effects of UVA on non-transformed immortalized keratinocytes (HaCaT cells), bearing potentially oncogenic mutations. We showed that UVA induces proteome remodeling and senescence in primary keratinocytes, eliciting potent antioxidant and pro-inflammatory responses. Additionally, we showed that UVA modulates the secretory phenotype of these cells to the extent of inducing paracrine oxidative stress and immune system activation in pre-malignant keratinocytes. These observations offer insights into the cellular mechanisms by which UVA drives photoaging in the skin.

Protocol for a Systematic Review on the Effectiveness of Interventions to Reduce Exposure to Occupational Solar UltraViolet Radiation (UVR) Among Outdoor Workers

Background: Solar UltraViolet Radiation (UVR) is considered the most relevant occupational carcinogenic exposure in terms of the number of workers exposed (i.e., outdoor workers) and UVR-induced skin cancers are among the most frequent types of occupational cancers worldwide. This review aims to collect and evaluate all the available preventive interventions conducted on outdoor workers to reduce their solar UVR related risk, with the final purpose of reducing the burden of occupational skin cancers for outdoor workers.Methods: We will search the following databases for peer-reviewed original research published: MEDLINE (through PubMed), Scopus, and EMBASE. We will include only interventional studies, both randomized and non-randomized, with an adequate comparison group, therefore excluding cross-sectional studies, as well as case-reports/series, reviews, and letters/comments. The systematic review will adhere to the “Preferred Reporting Items for Systematic reviews and Meta-Analyses” (PRISMA) guidelines for reporting systematic reviews. After the literature search, studies to be included will be independently reviewed by two Authors, first based on title and abstract, then based on the full text, according to the inclusion criteria. Conflicts will be solved by a third Author. Two authors will independently extract the required data from included studies and perform quality assessment according to the relevant domain for Risk of Bias assessment proposed by the Cochrane collaboration group. In case of sufficient homogeneity of interventions and outcomes evaluated, results from subgroups of studies will be pooled together in a meta-analysis.Discussion: Following the principles for the evaluation of interventions for cancer prevention established by the International Agency for Research on Cancer, this systematic review will investigate the effectiveness of the interventions, and consequently it will provide reliable indications for the actual reduction of skin cancer incidence in outdoor workers.

Prognostic factors of head and neck cutaneous squamous cell carcinoma: a systematic review

Background Head and neck cutaneous squamous cell carcinoma (HNCSCC) is a non-melanoma skin cancer that is mostly caused by solar ultraviolet radiation exposure. While it usually has an excellent prognosis, a subset of patients (5%) develops nodal metastasis and has poor outcomes. The aim of this study was to systematically review the literature and evaluate the prognostic factors of HNCSCC in order to better understand which patients are the most likely to develop metastatic disease. Methods A comprehensive literature search was performed on PubMed and EMBASE to identify the studies that evaluated the prognostic factors of HNCSCC. Prognostic factors were deemed significant if they had a reported p-value of < 0.05. Proportions of studies that reported a given factor to be statistically significant were calculated for each prognostic factor. Results The search yielded a total of 958 citations. Forty studies, involving a total of 8535 patients, were included in the final analysis. The pre-operative/clinical prognostic factors with the highest proportion of significance were state of immunosuppression (73.3%) and age (53.3%); while post-operative/pathological prognostic factors of importance were number of lymph nodes involved with carcinoma (70.0%), margins involved with carcinoma (66.7%), and tumor depth (50.0%). Conclusion This systematic review is aimed to aid physicians in assessing the prognosis of HNCSCC and identifying the subsets of patients that are most susceptible to metastasis. It also suggests that immunosuppressed patients with a high-risk feature on biopsy, such as invasion beyond subcutaneous fat, could possibly benefit from a sentinel lymph node biopsy. Graphical abstract

Bringing Light into Darkness—Comparison of Different Personal Dosimeters for Assessment of Solar Ultraviolet Exposure

(1) Measuring personal exposure to solar ultraviolet radiation (UVR) poses a major challenges for researchers. Often, the study design determines the measuring devices that can be used, be it the duration of measurements or size restrictions on different body parts. It is therefore of great importance that measuring devices produce comparable results despite technical differences and modes of operation. Particularly when measurement results from different studies dealing with personal UV exposure are to be compared with each other, the need for intercomparability and intercalibration factors between different measurement systems becomes significant. (2) Three commonly used dosimeter types—(polysulphone film (PSF), biological, and electronic dosimeters)—were selected to perform intercalibration measurements. They differ in measurement principle and sensitivity, measurement accuracy, and susceptibility to inaccuracies. The aim was to derive intercalibration factors for these dosimeter types. (3) While a calibration factor between PSF and electronic dosimeters of about 1.3 could be derived for direct irradiation of the dosimeters, this was not the case for larger angles of incidence of solar radiation with increasing fractions of diffuse irradiation. Electronic dosimeters show small standard deviation across all measurements. For biological dosimeters, no intercalibration factor could be found with respect to PSF and electronic dosimeters. In a use case, the relation between steady-state measurements and personal measurements was studied. On average, persons acquired only a small fraction of the ambient radiation.