Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem ter 1., Elettudomanyi Epulet, H-4032, Debrecen, Hungary.
The Hungarian Academy of Sciences, Center of Excellence, Budapest, Hungary.
J Mol Med (Berl). 2023 Aug;101(8):987-999. doi: 10.1007/s00109-023-02338-z. Epub 2023 Jun 23.
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.
聚（ADP-核糖）聚合酶 2（PARP2）与 PARP1 一起负责细胞中大部分的 PARP 活性，它们最初被描述为 DNA 修复因子。然而，过去几十年的研究表明，PARPs 在细胞能量调节、脂质稳态、细胞死亡和炎症等多种生物学功能中发挥作用。PARP 激活被描述为 Th2 介导的炎症过程，但研究集中在 PARP1 的作用上，而我们对 PARP2 在炎症调节中的作用知之甚少。在这项研究中，我们评估了 PARP2 在 Th17 介导的炎症性皮肤疾病银屑病中的作用。我们发现 PARP2mRNA 的表达在人银屑病皮损中增加。因此，我们在小鼠和细胞人银屑病模型中研究了 PARP2 表达降低的功能后果。我们观察到 PARP2 的缺失减弱了咪喹莫特诱导的小鼠银屑病样皮炎。沉默人角质形成细胞中的 PARP2 可防止其过度增殖，维持其终末分化，并减少它们在模拟银屑病的细胞因子 IL17A 和 TNFα 处理后产生炎症介质。在这些观察结果的基础上，我们发现芳香酶在 PARP2 敲除小鼠和 PARP2 缺陷型人角质形成细胞的表皮中被诱导，由此产生的更高的雌二醇产生抑制了 NF-κB 的激活，从而抑制了角质形成细胞中的炎症。甾体生成的改变以前在银屑病中被描述过，我们通过显示芳香酶在银屑病皮损中的表达减少来扩展这些观察结果。总之，我们的数据将 PARP2 鉴定为表皮角质形成细胞中雌激素生物合成的调节剂，这可能与 Th17 型炎症有关。
PARP2mRNA 的表达在银屑病患者的皮损中增加。
小鼠中 PARP2 的缺失减弱了咪喹莫特诱导的银屑病样皮炎。
PARP2 缺陷型人角质形成细胞中 NF-κB 的激活受到抑制。
PARP2 缺陷型角质形成细胞中更高的雌二醇具有抗炎作用。
