Endothelial Response to Type I Interferon Contributes to Vasculopathy and Fibrosis and Predicts Disease Progression of Systemic Sclerosis
Endothelial Response to Type I Interferon Contributes to Vasculopathy and Fibrosis and Predicts Disease Progression of Systemic Sclerosis
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DOI：
10.1002/art.42662
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发表时间：
2024-01-01
影响因子：
13.3
通讯作者：
Lu，Liangjing
中科院分区：
文献类型：
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作者：
Yin，Hanlin;Distler，Oliver;Lu，Liangjing
干扰素（IFN）-1特征是系统性硬化症（SSc）患者的标志。然而，其在临床分层和恶化的贡献的意义仍然需要更好地understood.MethodsFor hypothesis generation，我们进行了单细胞RNA测序（scRNA-seq）皮肤活检（4例SSc和2例对照）使用BD Rhapsody平台。使用两个公开可用的皮肤scRNA-seq数据集进行验证（GSE 138669：12例弥漫性皮肤SSc [dcSSc]患者和10例对照; GSE 195452：52例dcSSc患者和41例局限性皮肤SSc [lcSSc]患者和54例对照）。在博来霉素加IFNα-2腺病毒相关病毒（AAV）诱导的模型中对IFN-1特征进行了定位、功能研究，并在SSc队列（n = 61）中进行了验证。在真皮非免疫细胞中，内皮细胞（EC）具有最突出的IFN-1特征。与对照组相比，SSc患者和dcSSc患者与lcSSc患者相比，EC IFN-1特征均增加。在EC亚群中，IFN-1特征在dcSSc患者的毛细血管EC中统计学上更高，高于lcSSc患者，而lcSSc患者又高于健康对照（HC）。内皮-间质转化（EndoMT）评分平行增加。恶化博来霉素诱导的真皮纤维化、EndoMT和血管周围纤维化，并导致血管损失伴EC凋亡。血管粘病毒抗性（MX）1，一种IFN-1应答蛋白，在总SSc与HC皮肤和dcSSc与lcSSc皮肤中均显著增加。基线血管MX 1表现相似的皮肤评分在预测疾病进展超过6至34个月的总SSc和上级在dcSSc subpopulation.ConclusionThe EC IFN-1签名区分SSc皮肤亚型和疾病进展，并可能有助于血管病变和纤维化。
ObjectiveInterferon (IFN)‐1 signatures are a hallmark of patients with systemic sclerosis (SSc). However, its significance in clinical stratification and contribution to deterioration still need to be better understood.MethodsFor hypothesis generation, we performed single‐cell RNA sequencing (scRNA‐seq) on skin biopsies (four patients with SSc and two controls) using the BD Rhapsody platform. Two publicly available data sets of skin scRNA‐seq were used for validation (GSE138669: 12 patients with diffuse cutaneous SSc [dcSSc] and 10 controls; GSE195452: 52 patients with dcSSc and 41 patients with limited cutaneous SSc [lcSSc] and 54 controls). The IFN‐1 signature was mapped, functionally investigated in a bleomycin plus IFNα‐2 adenovirus‐associated virus (AAV)–induced model and verified in an SSc cohort (n = 61).ResultsThe discovery and validation data sets showed similar findings. Endothelial cells (ECs) had the most prominent IFN‐1 signature among dermal nonimmune cells. The EC IFN‐1 signature was increased both in patients with SSc versus controls and in patients with dcSSc versus those with lcSSc. Among EC subclusters, the IFN‐1 signature was statistically higher in the capillary ECs of patients with dcSSc, which was higher than those in patients with lcSSc, which in turn was higher than those in healthy controls (HCs). Endothelial‐to‐mesenchymal transition (EndoMT) scores increased in parallel. Deteriorated bleomycin‐induced dermal fibrosis, EndoMT, and perivascular fibrosis and caused blood vessel loss with EC apoptosis. Vascular myxovirus resistance (MX) 1, an IFN‐1 response protein, was significantly increased both in total SSc versus HC skin and in dcSSc versus lcSSc skin. Baseline vascular MX1 performed similarly to skin score in predicting disease progression over 6 to 34 months in total SSc and was superior in the dcSSc subpopulation.ConclusionThe EC IFN‐1 signature distinguished SSc skin subtypes and disease progression and may contribute to vasculopathy and fibrosis.