Poly (ADP) Ribose Polymerase (PARP)‐1 Is A critical Determinant of Atopic Dermatitis through Control of Allergen‐Induced Th2 And T‐regulatory Responses And Expression of The Matricellular Protein Periostin

Abstract

BackgroundAtopic dermatitis (AD) is a complex and multi‐factorial chronic inflammatory skin disorder. Individuals with AD have limited treatment options and, thus, identifying the key molecular mechanisms that participate in the pathogenesis of the disease will increase the likelihood of establishing precise strategies to prevent/combat the debilitating symptoms of AD. Immune system defects, including deregulated Th2 responses and hyperproduction of IgE, play a key role in the progression of the disease. Increasing evidence shows that the extracellular matrix (ECM) protein periostin plays an equally important role in AD. Our laboratory has extensively examined the role of PARP‐1 in the pathogenesis of several inflammatory diseases including chronic allergic asthma. PARP‐1 inhibition genetically or pharmacologically by Olaparib, a drug that is currently being used as a monotherapy against human ovarian cancer, provides a significant protection against the onset of the disease by blocking Th2 cytokines and IgE production and several other related factors.ObjectiveTo examined the efficacy of PARP‐1 inhibition by gene deletion or by Olaparib against AD traits using both an in vitro and an animal model of the disease.MethodsWild type and PARP‐1−/− mice were epicutaneously exposed to ovalbumin (OVA) 3 times a week for 3 weeks; each week was separated by a 2‐week resting period. Olparib (5mg/kg) was injected to WT mice. At the end of the protocol, the severity of dermatitis was evaluated using a clinical skin scoring (CSS) system. Mice were euthanized; skin biopsies were analyzed for immunohistopathologic features. Serum were collected and assessed for OVA‐specific IgE and cytokines levels. Spleen‐derived cells were assessed by FACS. WT or PARP‐1−/− skin fibroblasts were treated with LPS or IL‐13 for different time intervals then subjected to RT‐PCR or immunoblot analysis.ResultsPARP inhibition by gene knockout or pharmacologically by Olaparib provided a robust reduction in the manifestation of all traits of the disease including Redness, thickness, scratching and lichenification as assessed by the Eczema Area and Severity Index (EASI). The protective effects of PARP inhibition may be mediated by a differential regulation of Th1/Th2 cytokines production. Indeed, while PARP inhibition suppressed production of Th2 cytokines (e.g. IL‐4/IL‐5/GM‐CSF) and allergen‐specific IgE, it exerted no effect on production of the anti‐inflammatory cytokine IL‐10 or the Th1 cytokine, IFN‐γ. Such differential effects occurred with a statistically significant increase in T‐regulatory cell population. Remarkably, PARP‐1 appeared to play a critical role in periostin protein expression both in vitro using skin fibroblasts and in the skin of mice using the AD animal model. PARP‐1 inhibition may not only alter the function and ability of T cells to produce Th2 cytokines but also regulate the production of the ECM proteins as periostin.ConclusionOur results show for the first time that PARP‐1 plays a critical role in atopic dermatitis. These findings provide evidence for the potential of PARP‐1 inhibitors as a novel therapeutic strategy and Olaparib as a likely candidate to be tested in human clinical trials.Support or Funding InformationNIH