Acta Dermato-Venereologica 2018, No. 6 98-6CompleteContent

576 INVESTIGATIVE REPORT 8-Methoxypsoralen Plus Ultraviolet A Reduces the Psoriatic Response to Imiquimod in a Murine Model Nitesh SHIRSATH 1 , Karin WAGNER 2 , Simone TANGERMANN 3 , Michaela SCHLEDERER 4 , Christian RINGEL 5 , Lukas KENNER 3,4,6 , Bernhard BRÜNE 5 and Peter WOLF 1 Research Unit for Photodermatology, Department of Dermatology and Venereology, 2 Center for Medical Research, Medical University of Graz, Graz, 3 Unit of Laboratory Animal Pathology, University of Veterinary Medicine, 4 Department of Pathology, Department of Experimental and Laboratory Animal Pathology, Medical University Vienna, Vienna, Austria, 5 Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany, and 6 Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria 1 The effects of 8-Methoxypsoralen plus ultraviolet A (PUVA) or ultraviolet B (UVB) alone on imiquimod- induced psoriasis were examined in a mouse model. Mouse skin was treated with repetitive sub-phototoxic doses of PUVA or UVB before or during the induction of toll-like receptor 7/8 activation and psoriasis th- rough the application of imiquimod. PUVA, to a greater degree than UVB, suppressed the established imiqui- mod-induced psoriatic phenotype, but pretreatment with PUVA prior to administration of imiquimod also reduced the susceptibility of murine skin to respond to imiquimod to a greater degree than did pretreatment with UVB. PUVA downregulated baseline levels of miR- NA27a and 29a, as well as interferon-γ, interleukin-17 and -9, cytokines, which drive psoriatic inflammation. Microarray analysis showed enrichment of senes- cence pathway genes linked to upregulation of p16/ p21 proteins after PUVA pretreatment. However, the anti-psoriatic effect of PUVA was lost when there was an interval of 7 days between final exposure to PUVA and the start of administration of imiquimod. This in- dicated that (UVB and) PUVA diminished imiquimod- induced established psoriatic inflammation, but also primed the skin in favour of a reduced responsiveness to toll-like receptor activation. Key words: psoriasis; PUVA; UVB; imiquimod; interleukin-9, senescence. Accepted Feb 13, 2018; Epub ahead of print Feb 13, 2018 Acta Derm Venereol 2018; 98: 576–584. Corr: Peter Wolf, Department of Dermatology, Medical University of Graz, Auenbruggerplatz 8, AT-8036 Graz, Austria. E-mail: peter.wo lf@medu- nigraz.at 8 -Methoxypsoralen plus ultraviolet A (PUVA) or ultraviolet B (UVB) alone are well-established and effective phototherapeutic treatments for mild to severe psoriasis (1–6). However, the exact therapeutic mechanism(s) of phototherapy in psoriasis is unknown (7, 8). Phototherapy has both proapoptotic and immu- nomodulatory actions, which may, singly or together, be responsible for its therapeutic efficacy (9, 10). Exposure to UV radiation (with or without psoralen photosensiti- zation) is immunosuppressive at the local and even the systemic level, depending on the dose administered (11– 14). Similar to biologics, several studies have indicated doi: 10.2340/00015555-2905 Acta Derm Venereol 2018; 98: 576–584 that UVB and PUVA photochemotherapy downregulate the interleukin (IL)-23/T-helper (Th)17 axis, which is thought to be the essential driver in the pathophysiology of psoriasis (15–19). However, a mathematical model has suggested that keratinocyte apoptosis and elimination alone may be responsible for the therapeutic effects of UVB treatment (20). The aim of the current study was to investigate the mechanism of phototherapy in an imiquimod (IMQ) psoriasis model (21). Topical application of IMQ on the skin of humans and mice induces inflammation and pathology, which closely resembles plaque-type psoriasis (22). The immunomodulatory effects of IMQ are predo- minantly attributed to stimulation of toll-like receptor (TLR) 7/8 on plasmacytoid dendritic cells (pDCs). This IMQ-induced inflammation leads to production of large amounts of type I interferons (IFNs) from pDCs, along with interleukin (IL)-23 and IL-17RA signalling and IL- 22. Thus, the IMQ mouse model enables research into the development and persistence of psoriasis, which would be difficult in patients (23). To date, the IMQ model has helped to increase our knowledge of the early pathophy- siology of psoriasis (21). The action of tumour necrosis factor (TNF) antagonists (including adalimumab, etaner- cept and infliximab), and other important anti-cytokine antibodies, such as anti-IL-17 mAb, as well as IL-4, rapamycin, and narrow-band ultraviolet B (NB-UVB) have been examined with this model (19, 24–28). MATERIALS AND METHODS Animals and psoriatic model BALB/c mice were purchased from Charles-River, Sulzfed, Ger- many and housed in the animal facility of the Centre for Medical Research, Medical University of Graz, Austria. All procedures to which the mice were subjected were approved by the Austrian Government, Federal Ministry for Science and Research (protocol number BMWF-66-010/0032-11/3b/2013). Female mice aged 7–8 weeks had their back skin shaved 48 h before the start of the study. Aldara ® (IMQ) 5% cream (MEDA Pharmaceuticals, Vienna, Austria) was used to induce psoriatic skin changes on the shaved back of the mice, as described previously (28). A total amount of 62.5 mg IMQ per treatment and mouse was applied in the morning whereas PUVA or UVB treatment, when given on the same days, was administered in the afternoon at an interval of 6 h after IMQ administration. All animals were maintained with alternating 12-h light-and-dark cycles and at controlled temperature and humidity This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2018 Acta Dermato-Venereologica.

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