Poly (ADP) Ribose Polymerase (PARP)-1 as a novel therapeutic target for alleviating the manifestations of Atopic Dermatitis

Abstract ID 102930 Poster Board 006 Background: Atopic dermatitis (AD) is a multifaceted and multifactorial chronic inflammatory skin disorder. Patients with AD have few treatment choices. Therefore, understanding the main molecular pathways involved in the development of the illness would improve the chances of developing effective therapies to prevent or treat the disease. AD is driven by immune system abnormalities, including dysregulated Th2 responses and excessive synthesis of IgE. Mounting data indicates that the extracellular matrix (ECM) protein periostin has a significant function in AD. Our group has thoroughly investigated the involvement of PARP-1 in the development of several chronic inflammatory conditions, such as allergic asthma. We reported that PARP-1 inhibition, either by genetic means or with Olaparib, effectively protects against the development of AD. Such protection is achieved by preventing the generation of Th2 cytokines, IgE, and other associated components. Objective: To assess whether PARP-1 inhibition by gene deletion or Olaparib would be effective in mitigating the progression of AD in both n vitro and the in vivo model of the diseases. Method: Wild-type and PARP-1−/− mice were subjected to epicutaneous exposure to ovalbumin (OVA) three times per week for a duration of three weeks, with each week being followed by a two-week resting period. WT mice were administered Olparib at a dosage of 5mg/kg. Following the protocol's completion, the degree of dermatitis was assessed utilizing a clinical skin scoring (CSS) technique. The mice were euthanized, and skin biopsies were examined by IHC. Serum samples were obtained and analyzed for levels of OVA-specific IgE and cytokines. Cells obtained from the spleen were evaluated using flow cytometry. WT or PARP-1−/− skin fibroblasts were exposed to LPS or IL-13 for varying durations and subsequently analyzed using RT-PCR or immunoblot techniques. Results: Utilizing the Eczema Area and Severity Index (EASI) clinical scoring system, we found that PARP-1 inhibition by gene deletion or pharmacologically by Olaparib effectively reduced the disease manifestations, including redness, thickness, itching, and lichenification. Such effects may be achieved by altering Th1/Th2 cytokine production. PARP-1 inhibition effectively reduced the production of Th2 cytokines (such as IL-4, IL-5, and GM-CSF) and allergen-specific IgE ewithout any effect on the production of the anti-inflammatory cytokine IL-10 or the Th1 cytokine, IFN-γ. These differential effects resulted in a statistically significant increase in the number of T-regulatory cells and a downregulation in the expression of periostin protein. These findings suggest that inhibiting PARP-1 might potentially affect the function of T cells to generate Th2 cytokines, as well as control the formation of extracellular matrix (ECM) proteins such as periostin. Conclusion: Our findings provide evidence for the potential of PARP-1 inhibitors as a novel therapeutic approach and Olaparib as a likely candidate to be tested in human clinical trials for the treatment of Atopic Dermatitis.