Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Cell Rep. 2020 Nov 17;33(7):108407. doi: 10.1016/j.celrep.2020.108407.
Individuals with Down syndrome (DS; trisomy 21) display hyperactivation of interferon (IFN) signaling and chronic inflammation, which could potentially be explained by the extra copy of four IFN receptor (IFNR) genes encoded on chromosome 21. However, the clinical effects of IFN hyperactivity in DS remain undefined. Here, we report that a commonly used mouse model of DS overexpresses IFNR genes and shows hypersensitivity to IFN ligands in diverse immune cell types. When treated repeatedly with a TLR3 agonist to induce chronic inflammation, these animals overexpress key IFN-stimulated genes, induce cytokine production, exhibit liver pathology, and undergo rapid weight loss. Importantly, the lethal immune hypersensitivity and cytokine production and the ensuing pathology are ameliorated by JAK1 inhibition. These results indicate that individuals with DS may experience harmful hyperinflammation upon IFN-inducing immune stimuli, as observed during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, pointing to JAK1 inhibition as a strategy to restore immune homeostasis in DS.
唐氏综合征（DS；21 三体）患者表现出干扰素（IFN）信号的过度激活和慢性炎症，这可能可以通过 21 号染色体上额外的四个 IFN 受体（IFNR）基因拷贝来解释。然而，DS 中 IFN 过度活跃的临床影响仍未定义。在这里，我们报告说，一种常用的 DS 小鼠模型过度表达 IFNR 基因，并在各种免疫细胞类型中对 IFN 配体表现出超敏反应。当用 TLR3 激动剂反复处理以诱导慢性炎症时，这些动物过度表达关键的 IFN 刺激基因，诱导细胞因子产生，表现出肝病理，并迅速体重减轻。重要的是，通过 JAK1 抑制可以改善致命的免疫过敏和细胞因子产生以及随之而来的病理。这些结果表明，DS 患者在受到 IFN 诱导的免疫刺激时可能会经历有害的过度炎症，如在严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）感染期间观察到的那样，这表明 JAK1 抑制是恢复 DS 中免疫稳态的一种策略。
