HIF-1α and miR-210 differential and lineage-specific expression in systemic lupus erythematosus.
HIF-1α and miR-210 differential and lineage-specific expression in systemic lupus erythematosus.
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DOI：
10.1016/j.molimm.2021.02.019
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发表时间：
2021-05
影响因子：
3.6
通讯作者：
Kiriakidou M
中科院分区：
文献类型：
--
作者：
Garchow B;Maque Acosta Y;Kiriakidou M
系统性红斑狼疮（SLE，lupus）是一种慢性自身免疫性疾病，其特征是外周对核自身抗原的耐受性丧失。越来越多的人认识到异常的T细胞代谢是SLE免疫病理学的关键介质。缺氧诱导因子1α（HIF-1 α）是调节T细胞代谢的关键转录因子。T细胞活化诱导HIF-1α表达和HIF应答基因的转录激活。HypoxamiR是一组对HIF-1α转录调控敏感的microRNA，其功能是微调HIF驱动的转录程序。“主”hypoxamiR，miR-210受HIF-1α转录调控，并负调控HIF-1α活性。虽然HIF-1α在许多自身免疫性和炎症性疾病中的关键作用已经被描述，并且异常microRNA表达谱与许多风湿性疾病的不良临床结果相关，但HIF-1α和miR-210在狼疮中的表达和功能在很大程度上仍然没有被表征。在这里，我们报告HIF-1α和miR-210的差异和谱系特异性表达系统性红斑狼疮。我们发现HIF-1α mRNA和蛋白在人狼疮CD 4+细胞中过表达，但在CD 8+或CD 19+细胞中不表达。RORγt在人类狼疮淋巴细胞中上调，而FoxP 3表达保持不变。我们发现，miR-210在狼疮易感小鼠中的表达与疾病活动相关，并且在来自人类狼疮患者和狼疮易感小鼠的CD 4+细胞中强烈且选择性地上调。提示HIF-1α和miR-210的异常表达参与了SLE的免疫病理过程，HIF-1α/miR-210可能是SLE免疫调节的一个新的重要轴。
Systemic lupus erythematosus (SLE, lupus) is a chronic autoimmune disease characterized by loss of peripheral tolerance to nuclear self-antigens. It is increasingly recognized that aberrant T cell metabolism is a critical mediator of SLE immunopathology. Hypoxia inducible factor 1α (HIF-lα) is a key transcription factor that regulates T cell metabolism in response to immune stimuli. T cell activation induces HIF-1α expression and transcriptional activation of HIF-responsive genes. HypoxamiRs are a group of microRNAs sensitive to HIF-1α transcriptional regulation that function to fine-tune the HIF-driven transcriptional program. The ‘master’ hypoxamiR, miR-210 is transcriptionally regulated by HIF-1α and negatively regulates HIF-1α activity. Although a key role for HIF-1α in has been described in a number of autoimmune and inflammatory diseases and abnormal microRNA expression profiles correlate with poor clinical outcome in a number of rheumatologic diseases, the expression and function of HIF-1α and miR-210 in lupus remains largely uncharacterized. Here we report HIF-1α and miR-210 differential and lineage-specific expression in systemic lupus erythematosus. We show that HIF-1α mRNA and protein is overexpressed in human lupus CD4+ cells but not in CD8+ or CD19+ cells. RORγt, was upregulated in human lupus lymphocytes while FoxP3 expression remained unchanged. We show that miR-210 expression in lupus-prone mice correlates with disease activity and is robustly and selectively upregulated in CD4+ cells from both human lupus patients and lupus-prone mice. Our results suggest that abnormal HIF-1α and miR-210 expression contributes to SLE immune pathology and that HIF-1α/miR-210 may represent a novel and important regulatory axis in SLE.
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