Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA.
Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA.
FASEB J. 2022 Jun;36(6):e22336. doi: 10.1096/fj.202101436R.
Idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-associated interstitial lung disease (RA-ILD) are two fibrotic interstitial lung diseases that share the usual interstitial pneumonia (UIP) injury pattern. Here, we report that RNA sequencing of lung biopsies from patients with RA-ILD and IPF revealed shared and distinct disease-causing pathways. Analysis of transcriptomic data identified a JAK2 related JAK/STAT signaling pathway gene signature that distinguishes RA-UIP from idiopathic UIP. This was further confirmed by immunohistostaining, which identified JAK2 phosphorylation with two distinct forms of activation: a cytoplasmic form of JAK2 activation in most IPF cases (13/20) and a nuclear form of p-JAK2 in RA-UIP (5/5) and a minority of IPF (6/20) cases. Further immunohistostaining identified STAT5A&B as the downstream transcriptional activator for JAK2-mediated canonical signal transduction and phosphorylation of Tyr41 on histone H3 (H3Y41ph) as the downstream epigenetic regulation site for JAK2-mediated noncanonical signal transduction. Gene Set Enrichment Analysis (GSEA) of the RNA-Seq data further supported this shared pathogenic mechanism for the two diseases with the enrichment of STAT5A&B target gene sets as well as the JAK2 regulated H3Y41ph target gene set. This regulatory role of JAK2 in the pathogenesis of pulmonary fibrosis was further demonstrated by the attenuation of bleomycin-induced murine pulmonary fibrosis using a JAK2-selective pharmacological inhibitor CEP33779. In vitro studies with normal and IPF derived lung fibroblasts revealed a central role for JAK2 as an essential intermediary molecule in TGF-β-mediated myofibroblast trans-differentiation, proliferation, and extracellular matrix protein production. These observations support a crucial role for JAK2 as an intermediary molecule in fibrotic lung disease development.
特发性肺纤维化（IPF）和类风湿关节炎相关间质性肺病（RA-ILD）是两种纤维化性间质性肺病，它们具有相同的寻常型间质性肺炎（UIP）损伤模式。在这里，我们报告称，对 RA-ILD 和 IPF 患者的肺活检进行 RNA 测序揭示了共享和独特的致病途径。对转录组数据的分析确定了一个 JAK2 相关的 JAK/STAT 信号通路基因特征，该特征可将 RA-UIP 与特发性 UIP 区分开来。这进一步通过免疫组织化学染色得到证实，该染色鉴定了 JAK2 磷酸化的两种不同激活形式：大多数 IPF 病例（20 例中的 13 例）中的 JAK2 激活的细胞质形式和 RA-UIP（5 例中的 5 例）和少数 IPF（20 例中的 6 例）病例中的核形式的 p-JAK2。进一步的免疫组织化学染色鉴定出 STAT5A&B 是 JAK2 介导的经典信号转导的下游转录激活子，以及 JAK2 介导的非经典信号转导的组蛋白 H3 上 Tyr41 磷酸化（H3Y41ph）的下游表观遗传调节位点。RNA-Seq 数据的基因集富集分析（GSEA）进一步支持了这两种疾病的共同致病机制，STAT5A&B 靶基因集以及 JAK2 调节的 H3Y41ph 靶基因集的富集支持了这一机制。使用 JAK2 选择性药理学抑制剂 CEP33779 抑制博来霉素诱导的小鼠肺纤维化进一步证明了 JAK2 在肺纤维化发病机制中的调节作用。用正常和 IPF 来源的肺成纤维细胞进行的体外研究表明，JAK2 作为 TGF-β 介导的肌成纤维细胞转分化、增殖和细胞外基质蛋白产生的必需中间分子，发挥着核心作用。这些观察结果支持 JAK2 作为中间分子在纤维化性肺病发展中的关键作用。
