The transcriptional co-factor PARP14 limits severity of allergic skin inflammation

Abstract

Abstract Atopic dermatitis (AD) is a chronic relapsing inflammatory condition of the skin that is characterized by pruritic skin lesions, erythema, and swelling, resulting in an impaired skin barrier. Patients with AD and mice subjected to models of AD develop an inflammatory T helper 2 (Th2) immune response and reduced expression of epidermal differentiation complex (EDC) genes, which encode proteins needed for keratinocyte maturation and barrier integrity. We are exploring the molecular controls regulating Th2 cells and keratinocytes in a mouse model of AD. Poly-ADP ribose polymerse-14 (PARP14) is a transcription co-factor that enhances Th2 differentiation. Correspondingly, PARP14-deficient mice have reduced lung inflammation in a model of allergic airway disease; however, its potential role in AD has not been explored. In keratinocytes, PARP enzymatic activity does not alter expression of EDC genes. Surprisingly, PARP14 deficiency resulted in an increase in the severity and number of skin lesions in an experimental mouse model of AD. Disease severity and increasing age corresponded with increases in Th2 cytokine secretion and antibody production (IgE). Adoptive transfer of PARP14 deficient T cells from a mouse model of AD resulted in increase in alopecia, epidermal thickening and altered EDC gene expression. Thus, PARP14 serves opposing roles in allergic disease: promoting pathogenic Th2 immune responses in the lung while potentially limiting T cell-dependent inflammatory responses during skin inflammation.