Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Int Immunopharmacol. 2024 Aug 20;137:112503. doi: 10.1016/j.intimp.2024.112503. Epub 2024 Jun 20.
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.
银屑病被归类为一种自身免疫性疾病，其特征是异常的免疫反应导致慢性皮肤炎症的发展。大多数人都有遗传易感性，这种易感性可能会因多种变量（如污染物暴露）引起的表观遗传变化而进一步受到影响。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。邻苯二甲酸二（2-乙基己基）酯（DEHP）和银屑病炎症已知通过 DNA 甲基转移酶（DNMT）引起 DNA 甲基化的修饰。然而，尚不清楚 DEHP 是否通过 DNMT 调节影响银屑病炎症。因此，本研究调查了 DNA 甲基转移酶抑制剂 5-氮杂-2'-脱氧胞苷（AZA）对 DEHP 诱导的 DNMT1 表达、全基因组 DNA 甲基化和抗炎/促炎参数（p-STAT3、IL-17A、IL-6、iNOS、IL-10、Foxp3、Nrf2、HO-1）在皮肤和外周适应性/髓样免疫细胞（CD4+T 细胞/CD11b+细胞）中的变化的影响在咪喹莫特（IMQ）诱导的银屑病样炎症模型中。此外，还分析了咪喹莫特模型中与银屑病相关的临床/组织病理学特征（耳厚度、耳重、耳 PASI 评分、MPO 活性以及耳和背部皮肤的 H&E 染色）。我们的数据表明，在接受咪喹莫特治疗的小鼠中，DEHP 暴露会导致 DNMT1 表达增加和 DNA 甲基化增加，这与外周免疫细胞（CD4+T 细胞/CD11b+细胞）和皮肤中促炎（p-STAT3、IL-17A、IL-6、iNOS）和抗炎介质（IL-10、Foxp3、Nrf2、HO-1）水平升高有关。与接受咪喹莫特治疗的小鼠相比，DNMT1 抑制剂的治疗导致炎症参数降低，抗炎参数升高，同时接受咪喹莫特治疗和 DEHP 暴露的小鼠的临床/组织病理学症状也得到显著改善。总之，我们的研究表明，DNMT1 通过 DNA 超甲基化在 DEHP 诱导的小鼠银屑病样炎症加重中发挥重要作用。
