ISG15 deficiency features a complex cellular phenotype that responds to treatment with itaconate and derivatives.
ISG15 deficiency features a complex cellular phenotype that responds to treatment with itaconate and derivatives.
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ISG15缺乏症的特点是复杂的细胞表型，对衣康酸及其衍生物的治疗有反应。
DOI：
10.1002/ctm2.931
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发表时间：
2022-07
影响因子：
10.6
通讯作者：
中科院分区：
文献类型：
--
作者：
先天性ISG15缺乏症是一种罕见的自身炎症性疾病，由全身干扰素水平长期升高引起，主要影响中枢神经系统和皮肤。我们开发了诱导多能干细胞衍生的巨噬细胞和内皮细胞作为模型来研究ISG15缺乏症的细胞表型并确定新的治疗方法。ISG15 - / -巨噬细胞表现出预期的高炎症反应，但吞噬功能正常。此外，它们表现出多面性的病理表型，包括细胞凋亡/焦亡、氧化应激、糖酵解和酰基肉碱水平增加，但谷氨酰胺摄取、BCAT1表达、支链氨基酸分解代谢、氧化磷酸化、β氧化和NAD(P)H依赖性氧化还原酶活性降低。此外，ISG15 - / -细胞中参与线粒体生物发生和呼吸链复合物II-V的基因表达减少。有缺陷的线粒体呼吸可以通过野生型ISG15的转导得到恢复，但仅部分通过偶联缺陷变异得到恢复，这表明一些ISG15在线粒体呼吸中的功能需要对细胞靶点进行isg酰化。用衣康酸、二甲基衣康酸、4 -辛酯衣康酸和JAK1/2抑制剂鲁索利替尼治疗可改善增加的炎症、细胞死亡倾向和氧化应激。此外，这些处理大大改善了线粒体相关基因表达、BCAT1水平、氧化还原平衡以及细胞内和细胞外ATP水平。然而，根据读出量和细胞类型不同，化合物的功效不同，这表明它们对细胞靶点的作用并不相同。事实上，只有衣康酸盐增加了抗氧化基因NFE2L2、HMOX1和GPX7的表达，而衣康酸二甲酯改善氧化还原平衡的效果最大。尽管衣康酸治疗使干扰素刺激基因的升高表达正常化，但ISG15 - / -巨噬细胞对流感病毒感染的易感性仍然降低。这些发现扩大了人类ISG15缺乏症的细胞表型，揭示了ISG15在调节人类氧化应激、支链氨基酸代谢和线粒体功能方面的重要性。结果证实ruxolitinib可作为ISG15缺乏症的治疗方法，并建议以衣康酸为基础的药物作为这种罕见疾病的额外治疗方法。ISG15缺乏会引发过度炎症、细胞凋亡/焦亡和氧化应激，同时降低线粒体呼吸和生物发生、支链氨基酸分解代谢和病毒感染性。Itaconates和JAK1/2抑制剂ruxolitinib改善了这种失调的表型，确定它们是这种罕见疾病的潜在治疗选择。
Congenital ISG15 deficiency is a rare autoinflammatory disorder that is driven by chronically elevated systemic interferon levels and predominantly affects central nervous system and skin. We have developed induced pluripotent stem cell‐derived macrophages and endothelial cells as a model to study the cellular phenotype of ISG15 deficiency and identify novel treatments. ISG15–/– macrophages exhibited the expected hyperinflammatory responses, but normal phagocytic function. In addition, they displayed a multifaceted pathological phenotype featuring increased apoptosis/pyroptosis, oxidative stress, glycolysis, and acylcarnitine levels, but decreased glutamine uptake, BCAT1 expression, branched chain amino acid catabolism, oxidative phosphorylation, β‐oxidation, and NAD(P)H‐dependent oxidoreductase activity. Furthermore, expression of genes involved in mitochondrial biogenesis and respiratory chain complexes II–V was diminished in ISG15–/– cells. Defective mitochondrial respiration was restored by transduction with wild‐type ISG15, but only partially by a conjugation‐deficient variant, suggesting that some ISG15 functions in mitochondrial respiration require ISGylation to cellular targets. Treatment with itaconate, dimethyl‐itaconate, 4‐octyl‐itaconate, and the JAK1/2 inhibitor ruxolitinib ameliorated increased inflammation, propensity for cell death, and oxidative stress. Furthermore, the treatments greatly improved mitochondria‐related gene expression, BCAT1 levels, redox balance, and intracellular and extracellular ATP levels. However, efficacy differed among the compounds according to read‐out and cell type, suggesting that their effects on cellular targets are not identical. Indeed, only itaconates increased expression of anti‐oxidant genes NFE2L2, HMOX1, and GPX7, and dimethyl‐itaconate improved redox balance the most. Even though itaconate treatments normalized the elevated expression of interferon‐stimulated genes, ISG15–/– macrophages maintained their reduced susceptibility to influenza virus infection. These findings expand the cellular phenotype of human ISG15 deficiency and reveal the importance of ISG15 for regulating oxidative stress, branched chain amino acid metabolism, and mitochondrial function in humans. The results validate ruxolitinib as treatment for ISG15 deficiency and suggest itaconate‐based medications as additional therapeutics for this rare disorder. ISG15 deficiency triggers hyperinflammation, apoptosis/pyroptosis, and oxidative stress, while reducing mitochondrial respiration and biogenesis, branched chain amino acid catabolism, and viral infectivity. Itaconates and the JAK1/2 inhibitor ruxolitinib ameliorate this dysregulated phenotype, identifying them as potential therapeutic options for this rare disorder.
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期刊：
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影响因子：
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