BACKGROUND Although multiple studies have assessed molecular changes in chronic atopic dermatitis (AD) lesions, little is known about the transition from acute to chronic disease stages, and the factors and mechanisms that shape chronic inflammatory activity. OBJECTIVES We sought to assess the global transcriptome changes that characterize the progression from acute to chronic stages of AD. METHODS We analyzed transcriptome changes in paired nonlesional skin, acute and chronic AD lesions from 11 patients and 38 healthy controls by RNA-sequencing, and conducted in vivo and histological assays to evaluate findings. RESULTS Our data demonstrate that approximately 74% of the genes dysregulated in acute lesions remain or are further dysregulated in chronic lesions, whereas only 34% of the genes dysregulated in chronic lesions are altered already in the acute stage. Nonlesional AD skin exhibited enrichment of TNF, TH1, TH2, and TH17 response genes. Acute lesions showed marked dendritic-cell signatures and a prominent enrichment of TH1, TH2, and TH17 responses, along with increased IL-36 and thymic stromal lymphopoietin expression, which were further heightened in chronic lesions. In addition, genes involved in skin barrier repair, keratinocyte proliferation, wound healing, and negative regulation of T-cell activation showed a significant dysregulation in the chronic versus acute comparison. Furthermore, our data show progressive changes in vasculature and maturation of dendritic-cell subsets with chronicity, with FOXK1 acting as immune regulator. CONCLUSIONS Our results show that the changes accompanying the transition from nonlesional to acute to chronic inflammation in AD are quantitative rather than qualitative, with chronic AD having heightened TH2, TH1, TH17, and IL36 responses and skin barrier repair mechanisms. These findings provide novel insights and highlight underappreciated pathways in AD pathogenesis that may be amenable to therapeutic targeting.

中文翻译：

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急性至慢性特应性皮炎的进展与细胞因子反应的数量变化而非质量变化有关。

背景 尽管多项研究评估了慢性特应性皮炎 (AD) 病变的分子变化，但对于从急性到慢性疾病阶段的转变以及影响慢性炎症活动的因素和机制知之甚少。目标 我们试图评估表征 AD 从急性期到慢性期进展的全局转录组变化。方法 我们通过 RNA 测序分析了来自 11 名患者和 38 名健康对照者的成对非损伤性皮肤、急性和慢性 AD 损伤的转录组变化，并进行了体内和组织学检测以评估结果。结果我们的数据表明，大约 74% 的基因在急性病变中失调，在慢性病变中仍然存在或进一步失调，而只有 34% 在慢性病变中失调的基因在急性期已经改变。非损伤性 AD 皮肤表现出 TNF、TH1、TH2 和 TH17 反应基因的富集。急性病变显示出明显的树突细胞特征和 TH1、TH2 和 TH17 反应的显着富集，以及 IL-36 和胸腺基质淋巴细胞生成素表达增加，这在慢性病变中进一步增强。此外，涉及皮肤屏障修复、角质形成细胞增殖、伤口愈合和 T 细胞活化负调节的基因在慢性与急性比较中显示出显着的失调。此外，我们的数据显示，随着 FOXK1 充当免疫调节剂，脉管系统和树突细胞亚群的成熟逐渐发生变化。结论 我们的结果表明，伴随 AD 从非损伤性炎症到急性炎症再到慢性炎症转变的变化是定量的而不是定性的，慢性 AD 增强了 TH2、TH1、TH17 和 IL36 反应以及皮肤屏障修复机制。这些发现提供了新的见解，并突出了 AD 发病机制中未被充分认识的途径，这些途径可能适合治疗靶向。