PARP2 promotes inflammation in psoriasis by modulating estradiol biosynthesis in keratinocytes

ABSTRACT: Poly(ADP-ribose) polymerase 2 (PARP2) alongside PARP1 are responsible for the bulk of cellular PARP activity, and they were first described as DNA repair factors. However, research in past decades implicated PARPs in biological functions as diverse as the regulation of cellular energetics, lipid homeostasis, cell death, and inflammation. PARP activation was described in Th2-mediated inflammatory processes, but studies focused on the role of PARP1, while we have little information on PARP2 in inflammatory regulation. In this study, we assessed the role of PARP2 in a Th17-mediated inflammatory skin condition, psoriasis. We found that PARP2 mRNA expression is increased in human psoriatic lesions. Therefore, we studied the functional consequence of decreased PARP2 expression in murine and cellular human models of psoriasis. We observed that the deletion of PARP2 attenuated the imiquimod-induced psoriasis-like dermatitis in mice. Silencing of PARP2 in human keratinocytes prevented their hyperproliferation, maintained their terminal differentiation, and reduced their production of inflammatory mediators after treatment with psoriasis-mimicking cytokines IL17A and TNFα. Underlying these observations, we found that aromatase was induced in the epidermis of PARP2 knock-out mice and in PARP2-deficient human keratinocytes, and the resulting higher estradiol production suppressed NF-κB activation, and hence, inflammation in keratinocytes. Steroidogenic alterations have previously been described in psoriasis, and we extend these observations by showing that aromatase expression is reduced in psoriatic lesions. Collectively, our data identify PARP2 as a modulator of estrogen biosynthesis by epidermal keratinocytes that may be relevant in Th17 type inflammation. KEY MESSAGES: PARP2 mRNA expression is increased in lesional skin of psoriasis patients. PARP2 deletion in mice attenuated IMQ-induced psoriasis-like dermatitis. NF-κB activation is suppressed in PARP2-deficient human keratinocytes. Higher estradiol in PARP2-deficient keratinocytes conveys anti-inflammatory effect. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00109-023-02338-z.