Abstract：
Psoriasis is classified as an autoimmune disorder characterized by abnormal immune response leading to the development of chronic dermal inflammation. Most individuals have a genetic vulnerability that may be further influenced by epigenetic changes occurring due to multiple variables such as pollutant exposure. Epigenetic modifications such as DNA methylation possess a dynamic nature, enabling cellular differentiation and adaptation by controlling gene expression. Di(2-ethylhexyl) phthalate (DEHP) and psoriatic inflammation are known to cause modification of DNA methylation via DNA methyltransferase (DNMT). However, it is not known whether DEHP, a ubiquitous plasticizer affects psoriatic inflammation via DNMT modulation. Therefore, this study investigated the effect of DNMT inhibitor, 5-aza-2\'-deoxycytidine (AZA) on DEHP-induced changes in the expression of DNMT1, global DNA methylation, and anti-/inflammatory parameters (p-STAT3, IL-17A, IL-6, iNOS, IL-10, Foxp3, Nrf2, HO-1) in the skin and the peripheral adaptive/ myeloid immune cells (CD4+ T cells/CD11b+ cells) in imiquimod (IMQ) model of psoriasiform inflammation. Further, psoriasis-associated clinical/histopathological features (ear thickness, ear weight, ear PASI score, MPO activity, and H&E staining of the ear and the back skin) were also analyzed in IMQ model. Our data show that IMQ-treated mice with DEHP exposure had increased DNMT1 expression and DNA methylation which was associated with elevated inflammatory (p-STAT3, IL-17A, IL-6, iNOS) and downregulated anti-inflammatory mediators (IL-10, Foxp3, Nrf2, HO-1) in the peripheral immune cells (CD4+ T cells/CD11b+ cells) and the skin as compared to IMQ-treated mice. Treatment with DNMT1 inhibitor caused reduction in inflammatory and elevation in anti-inflammatory parameters with significant improvement in clinical/histopathological symptoms in both IMQ-treated and DEHP-exposed IMQ-treated mice. In conclusion, our study shows strong evidence indicating that DNMT1 plays an important role in DEHP-induced exacerbation of psoriasiform inflammation in mice through hypermethylation of DNA.
摘要：
银屑病被分类为自身免疫性疾病,其特征在于导致慢性皮肤炎症发展的异常免疫应答。大多数个体具有遗传脆弱性,其可能进一步受到由于诸如污染物暴露的多个变量而发生的表观遗传变化的影响。表观遗传修饰如DNA甲基化具有动态性质，通过控制基因表达来实现细胞分化和适应。已知邻苯二甲酸二(2-乙基己基)酯(DEHP)和银屑病炎症通过DNA甲基转移酶(DNMT)引起DNA甲基化的修饰。然而,不知道DEHP是否，普遍存在的增塑剂通过DNMT调节影响银屑病炎症。因此,这项研究调查了DNMT抑制剂的作用，5-氮杂-2'-脱氧胞苷（AZA）对DEHP诱导的DNMT1表达变化，全局DNA甲基化，和抗炎参数(p-STAT3，IL-17A，IL-6,iNOS,IL-10，Foxp3，Nrf2，HO-1）在银屑病样炎症的咪喹莫特（IMQ）模型中的皮肤和外周适应性/髓样免疫细胞（CD4T细胞/CD11b细胞）中。Further,银屑病相关临床/组织病理学特征(耳厚度，耳朵重量,耳朵PASI评分,MPO活动,以及耳朵和背部皮肤的H＆E染色）也在IMQ模型中进行了分析。我们的数据显示，用DEHP暴露的IMQ处理的小鼠DNMT1表达和DNA甲基化增加，这与炎症升高有关（p-STAT3，IL-17A，与IMQ处理的小鼠相比，外周免疫细胞（CD4T细胞/CD11b细胞）和皮肤中的IL-6，iNOS）和下调的抗炎介质（IL-10，Foxp3，Nrf2，HO-1）。在IMQ处理和DEHP暴露的IMQ处理的小鼠中,用DNMT1抑制剂处理引起炎症降低和抗炎参数升高,并且临床/组织病理学症状显著改善。总之,我们的研究表明,有强有力的证据表明,DNMT1在DEHP诱导的小鼠银屑病样炎症通过DNA高度甲基化加重中发挥重要作用.
