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

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.

Individualised computational modelling of immune mediated disease onset, flare and clearance in psoriasis

“…Importantly our model underscores the importance of apoptosis as an important mechanism in clearance of psoriasis in response to UVB. Together with data from our experimental studies [59,1] this suggests that targeting of apoptosis in drug development and therapeutic compound screening may prove useful. Additionally, our model distinguishes disease flares, and supports prediction of amending individual UVB phototherapy regimes based on the patient's initial response that include for example personalised delivery schedules (i.e., 3x weekly vs. 5x weekly phototherapy).…”

“…(These parameters will increase the activation rate of dendritic cells from their basal value dc act -see the equation for species DC in Eq. (1).) The parameters dc stim,i are fitted sequentially beginning with i = 1, and every parameter is searched incrementally in the interval [0, 6,000] starting at 0 with a step size of 60 (i.e., 100 increments).…”

“…When compared to the actual, observed behaviour (see Figure 6d), the patients in the Simulated Relapse group demonstrated a shorter remission period (median value of 3 months vs. 5 months, Kruskal-Wallis p-value=0.035) compared to the Simulated Remission group. (Simulated Relapse group: mean = 4.23, standard deviation = 4.17, range = [1,16] and IQR = [1.75, 6]; Simulated Remission group: mean = 6.45, standard deviation = 4.7, range = [1,18] and IQR = [3.75, 8.25]. )…”

Diet-Related Phototoxic Reactions in Psoriatic Patients Undergoing Phototherapy: Results from a Multicenter Prospective Study

“…Narrow-band ultraviolet B phototherapy (NB-UVB) represents a useful pre-biologics therapeutic option for psoriatic patients [21]. NB-UVB phototherapy may induce psoriasis clearance through pleiotropic effects on human cutaneous immunity, including the activation of apoptosis, DNA damage response and repair pathways, cell cycle control/differentiation and inflammation regulation [22]. Circadian rhythmicity disruption is also involved in psoriasis pathophysiology [23] and may influence NB-UVB response [22,24,25].…”

“…NB-UVB phototherapy may induce psoriasis clearance through pleiotropic effects on human cutaneous immunity, including the activation of apoptosis, DNA damage response and repair pathways, cell cycle control/differentiation and inflammation regulation [22]. Circadian rhythmicity disruption is also involved in psoriasis pathophysiology [23] and may influence NB-UVB response [22,24,25]. Furthermore, the concept that diet influences both inflammation and peripheral clocks is well established [16,17,26,27], but the impact of vegan and vegetarian diets on phototherapy remains neglected.…”