Pathogenic Th2 Cytokine Profile Skewing by IFN-γ-Responding Vitiligo Fibroblasts via CCL2/CCL8.
Pathogenic Th2 Cytokine Profile Skewing by IFN-γ-Responding Vitiligo Fibroblasts via CCL2/CCL8.
复制标题
通过CCL2/CCL8，通过IFN-γ反应的白癜风成纤维细胞串起致病性Th2细胞因子谱。
作者：
目的：白癜风是一种T细胞介导的皮肤色素脱失性疾病。虽然有阻止疾病进展和诱导色素沉着的治疗方法，但这些方法的疗效往往有限且持续性差。基质信号如何影响干扰素-γ-显性皮肤小生境尚不清楚。本研究旨在确定成纤维细胞如何参与IFN-γ主导的白癜风生态位。患者与方法：建立小鼠白癜风模型。提取来自对照和白癜风小鼠的成纤维细胞用于RNA测序。进行体外IFN-γ刺激以通过qPCR和Western印迹验证JAK-STAT途径。通过流式细胞术测量趋化因子的T细胞极化。还通过IHC检查了组织中的蛋白水平。结果：白癜风小鼠模型再现了人CD 8-IFN-γ通路。RNA测序显示白癜风成纤维细胞中趋化因子CCL 2和CCL 8升高，这可能是由JAK-STAT信号调节的。JAK抑制剂peficitinib在体外证实了这一现象。此外，将CCL 2加入到初始T极化系统中促进了2型细胞因子的分泌，这代表了白癜风病变的标志。结论：皮肤成纤维细胞是皮肤结构的主要组成部分，通过使T细胞通过CCL 2和CCL 8偏向2型细胞因子谱来响应IFN-γ，这可以被JAK抑制剂peficitinib消除。
Purpose: Vitiligo is a T cell-mediated skin depigmentation disease. Though treatments arresting disease progression and inducing repigmentation are available, the efficacy of these options is often limited and poorly sustained. How stromal signals contribute to the interferon-γ-dominant skin niches is unclear. This study aims to determine how fibroblasts participate in the IFN-γ-dominant vitiligo niche. Patients and methods: Mouse vitiligo models were established. Fibroblasts from control and vitiligo mice were extracted for RNA sequencing. In vitro IFN-γ stimulation was performed to verify the JAK-STAT pathway by qPCR and Western blot. T cell polarization with chemokines was measured by flow cytometry. Protein levels in tissues were also examined by IHC. Results: The vitiligo mouse model recapitulates the human CD8-IFN-γ pathway. RNA sequencing revealed elevated chemokine CCL2 and CCL8 in vitiligo fibroblast, which may be regulated by the JAK-STAT signaling. Such phenomenon is verified by JAK inhibitor peficitinib in vitro. Moreover, CCL2 addition into the naïve T polarization system promoted type 2 cytokines secretion, which represents a hallmark of vitiligo lesions. Conclusion: Dermal fibroblasts, a principal constituent of skin structure, respond to IFN-γ by skewing T cells towards a type 2 cytokine profile via CCL2 and CCL8, which can be abrogated by JAK inhibitor peficitinib.
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