Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 May:41:101924.
doi: 10.1016/j.redox.2021.101924. Epub 2021 Mar 10.

Therapeutic wavelengths of ultraviolet B radiation activate apoptotic, circadian rhythm, redox signalling and key canonical pathways in psoriatic epidermis

Rachel Addison  1 , Sophie C Weatherhead  2 , Anandika Pawitri  1 , Graham R Smith  3 , Ashley Rider  1 , Henry J Grantham  2 , Simon J Cockell  3 , Nick J Reynolds  4
Affiliations

Therapeutic wavelengths of ultraviolet B radiation activate apoptotic, circadian rhythm, redox signalling and key canonical pathways in psoriatic epidermis

Rachel Addison et al. Redox Biol. 2021 May.

Abstract

Ultraviolet B radiation (UVB) exerts pleiotropic effects on human skin. DNA damage response and repair pathways are activated by UVB; if damage cannot be repaired, apoptosis ensues. Although cumulative UVB exposure predisposes to skin cancer, UVB phototherapy is widely used as an effective treatment for psoriasis. Previous studies defined the therapeutic action spectrum of UVB and showed that psoriasis is resistant to apoptosis. This study aimed to investigate early molecular responses within psoriasis plaques following irradiation with single equi-erythemogenic doses of clinically-effective (311 nm, narrow-band) compared to clinically-ineffective (290 nm) UVB. Forty-eight micro-dissected epidermal samples from 20 psoriatic patients were analyzed using microarrays. Our bioinformatic analysis compared gene expression between 311 nm irradiated, 290 nm irradiated and control psoriasis epidermis to specifically identify 311 nm UVB differentially expressed genes (DEGs) and their upstream regulatory pathways. Key DEGs and pathways were validated by immunohistochemical analysis. There was a dynamic induction and repression of 311 nm UVB DEGs between 6 h and 18 h, only a limited number of DEGs maintained their designated expression status between time-points. Key disease and function pathways included apoptosis, cell death, cell migration and leucocyte chemotaxis. DNA damage response pathways, NRF2-mediated oxidative stress response and P53 signalling were key nodes, interconnecting apoptosis and cell cycle arrest. Interferon signalling, dendritic cell maturation, granulocyte adhesion and atherosclerotic pathways were also differentially regulated. Consistent with these findings, top transcriptional regulators of 311 nm UVB DEGs related to: a) apoptosis, DNA damage response and cell cycle control; b) innate/acquired immune regulation and inflammation; c) hypoxia/redox response and angiogenesis; d) circadian rhythmicity; f) EGR/AP1 signalling and keratinocyte differentiation; and g) mitochondrial biogenesis. This research provides important insights into the molecular targets of 311 nm UVB, underscoring key roles for apoptosis and cell death. These and the other key pathways delineated may be central to the therapeutic effects of 311 nm in psoriasis.

Keywords: Epidermal remodelling; Personalised therapy; Scalable biomarkers; Transcriptomics; UVB phototherapy; p53 signalling.

PubMed Disclaimer

Conflict of interest statement

NJR has received research grant funding from Novartis, PSORT partners (www.PSORT.org.uk); and income to Newcastle University from Almirall, Leo, Lilly and Novartis for attendance at advisory boards.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Study Overview. A) Schematic representation of irradiation protocol with either single exposure of 3 MEDs of 290 nm and/or 311 nm UVB to lesional psoriasis skin on the lower back. Six hours and/or 18 h later punch biopsies were taken from irradiated or unirradiated lesional psoriasis skin, microdissected, RNA extracted and subject to microarray and bioinformatic analysis. B) Venn diagrams showing DEGs derived from comparisons of 311 nm irradiated samples versus unirradiated controls, of 290 nm irradiated samples versus unirradiated controls, and 311 nm irradiated samples versus 290 nm irradiated samples at 6 h and 18 h. C) Numbers of upregulated and downregulated DEGs in each of the 3 key specified sectors (311 nm versus control, overlap and 311 nm versus 290 nm that comprise 311 nm UVB DEGs; excluding DEGs of 290 nm versus control) of the Venn Diagram. D) Alluvial plot showing the time course relationship of 311 nm UVB DEGs derived from the 3 key sectors (311 nm versus control, overlap and 311 nm versus 290 nm – excluding DEGs of 290 nm versus control) of the Venn diagram.
Fig. 2
Fig. 2
Canonical pathways, diseases,functions and transcriptional regulators identified by IPA for DEGs in lesional psoriasis skin in response to 311 nm UVB compared to 290 nm UVB. DEGs regulated by 311 nm UVB but not by 290 nm UVB (blue and purple sectors of Venn diagrams at 6 h (A) and 18 h (B) – 311 nm UVB DEGs) were analyzed by IPA. For diseases and function, the highest positive Z-scores and lowest negative Z-scores relating to the 311 nm DEGs (blue and purple sectors) are shown in upper and lower tables respectively for each time point. Canonical pathways differentially regulated by 311 nm compared to 290 nm (blue and purple sectors) are shown as horizontal bar graphs for each time point with Z-score represented by bar color. (C and D) Top transcriptional regulators differentially up-regulated (C) or down-regulated (D) by 311 nm at 6 h and 18 h are shown as heatmaps (C, darker orange represents greater expression and D) darker blue represents reduced expression at each time point). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
Fig. 3
311 nm UVB upregulates expression of nuclear FOSL1, GDF15, JUNB and CDKN1A in humanpsoriaticepidermis compared to 290 nmUVBand unirradiated control at 24 h. (A) Confocal images of immunostained sections from biopsies taken 24 h after irradiation of lesional psoriasis skin (Psor.) with 3 MEDs of 311 nm UVB, 290 nm UVB or unirradiated control, captured using a scanning confocal microscopy (Leica TCP SP8). Scale bars for all images 100 μm , x40 oil immersion lens). All images shown were taken from the same donor. Red fluorescent signal – nuclear dye (TO-PRO) and green signal (Alexa Fluor 488 nm). (B) Volocity analysis was performed to quantify epidermal signal per μm2 (mean ± SD from 3 independent donors) for biomarkers FOSL1, GDF15, JUNB and CDKN1A in 311 nm UVB irradiated lesional skin, 290 nm UVB irradiated lesional skin and unirradiated control. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 4
Fig. 4
Identification and visualisation of positive (A) and negative (B) upstream regulators of differentially expressed genes in lesional psoriasis skin induced by 311 nm UVB compared to 290 nm UVB at 6 h and 18 h after irradiation. Heat maps show standardised gene expression (logFC) as; red: increased expression; blue: decreased expression. Gene lists on the right of the heatmap show apoptotic genes differentially regulated by the top upstream transcriptional regulators depicted across the bottom of the figure. Green boxes demonstrate which regulators regulate their respected DEGs. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 4
Fig. 4
Identification and visualisation of positive (A) and negative (B) upstream regulators of differentially expressed genes in lesional psoriasis skin induced by 311 nm UVB compared to 290 nm UVB at 6 h and 18 h after irradiation. Heat maps show standardised gene expression (logFC) as; red: increased expression; blue: decreased expression. Gene lists on the right of the heatmap show apoptotic genes differentially regulated by the top upstream transcriptional regulators depicted across the bottom of the figure. Green boxes demonstrate which regulators regulate their respected DEGs. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 5
Fig. 5
Enriched canonical pathways of the DEGs associated with the p53 signalling pathway identified by IPA, showing gene expression and predicted relationships between top regulated 311 nm UVB DEGs at 6 h and 18 h post-irradiation. Signalling pathway regulation based on the analysis of (A) 755 DEGs at 6 h and (B) 795 DEGs at 18 h respectively. Blue lines between DEGs represent predicted inhibition between genes and orange lines represent predicted activation between DEGs based on our transcriptomic data. Red symbols denote increased gene expression and green gene symbols represent downregulation. Each symbol shape represents a different molecule type. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 6
Fig. 6
Enriched canonical pathway of IFN transcriptomic pathway identified by IPA, showing gene expression and predicted relationships between molecules differentially regulated by 311 nm UVB 18 h after irradiation. 311 nm UVB DEG expression and molecular relationships between 311 nm UVB DEGs predicted by using IPA molecular activity predictor using our transcriptomic data of 795 (18 h) DEGs. Transcriptomic data associated with apoptosis was applied to the IFN signalling pathway to identify any interconnectivity between IFN signalling and apoptosis. Blue lines between DEGs represent predicted inhibition between genes and orange represent predicted activation between DEGs based on our transcriptomic data. Red symbols denote increased gene expression. Each symbol shape represents a different molecule type. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Schuch A.P., Moreno N.C., Schuch N.J., Menck C.F.M., Garcia C.C.M. Sunlight damage to cellular DNA: focus on oxidatively generated lesions. Free Radic. Biol. Med. 2017;107:110–124. - PubMed
    1. Jagoda S.V., Dixon K.M. Protective effects of 1,25 dihydroxyvitamin D3 and its analogs on ultraviolet radiation-induced oxidative stress: a review. Redox Rep. 2020;25(1):11–16. - PMC - PubMed
    1. Murphy G., Young A.R., Wulf H.C., Kulms D., Schwarz T. The molecular determinants of sunburn cell formation. Exp. Dermatol. 2001;10(3):155–160. - PubMed
    1. Qin J.-Z., Chaturvedi V., Denning M.F., Bacon P., Panella J., Choubey D., Nickoloff B.J. Regulation of apoptosis by p53 in UV-irradiated human epidermis, psoriatic plaques and senescent keratinocytes. Oncogene. 2002;21(19):2991–3002. - PubMed
    1. Zhang S., Xia C., Xu C., Liu J., Zhu H., Yang Y., Xu F., Zhao J., Chang Y., Zhao Q. Early growth response 3 inhibits growth of hepatocellular carcinoma cells via upregulation of Fas ligand. Int. J. Oncol. 2017;50 - PubMed

Publication types