PDRN, a Biologic Agonist of the Adenosine A 2A Receptor, Ameliorates Imiquimod-Induced Psoriasis Through NF-κB Pathway Inhibition and Wnt/β-Catenin Signalling Modulation

Background: Inflammation is a key hallmark of psoriasis and pro-inflammatory cytokines are produced by the transcription factor Nuclear factor-κB (NF-κB). Canonical Wnt/β-catenin pathway blunts the immune-mediated inflammatory cascade in psoriasis. Adenosine A2A receptor activation either blocks NF-κB and boosts the Wnt/β-catenin signalling. PDRN (Polydeoxyribonucleotide) is a biologic agonist of the A2A receptor and its effects were studied in an experimental model of psoriasis. Methods: Psoriasis-like lesions were induced by a topical daily application of imiquimod cream (IMQ; 62.5 mg/day for 7 days) on the shaved back skin of mice. Animals were randomly assigned to the following groups: Sham psoriasis challenged with vaseline cream; IMQ animals challenged with imiquimod and IMQ animals challenged with IMQ and treated with PDRN (8 mg/kg/ip). In histological experiments an additional arm of IMQ animals was treated with PDRN plus istradefylline (KW6002; 25 mg/kg/ip) as an A2A antagonist. Findings: PDRN administration reduced squamous lesions, erythema, epidermal thickness and acanthosis, trying to restore a normal skin architecture. Istradefylline administration abrogated PDRN positive effects, thus pointing out the mechanistic role of the A2A receptor. PDRN decreased pNF-κB and TNF-α IL-6 and IL-12 expression compared to untreated psoriatic animals. Furthermore, A2Areceptor activation prompted Wnt signalling, reduced IL-2 expression and increased IL-10 mRNA expression in psoriatic skin. Finally, PDRN reduced CD3+ cells in superficial psoriatic dermis.   Interpretations: PDRN anti-psoriasis potential may be linked to a "dual mode" of action: NF-κB pathway inhibition and Wnt/β-catenin signalling stimulation. Funding: The work has been performed with Departmental funding assigned to FS. Competing Interest Declaration: The authors declare that the research was conducted in the absence of any commercial or financial conflict of interest. Ethics: The procedures were evaluated and approved by the Ethics Committee of the University of Messina (OPBA, #820/2016).