Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion, Greece; Laboratory of Autoimmunity and Inflammation, Faculty of Medicine, University of Crete, Heraklion, Greece.
Laboratory of Autoimmunity and Inflammation, Faculty of Medicine, University of Crete, Heraklion, Greece.
Cell Rep. 2018 Oct 23;25(4):921-933.e5. doi: 10.1016/j.celrep.2018.09.001.
Interferon α (IFNα) is a prompt and efficient orchestrator of host defense against nucleic acids but upon chronicity becomes a potent mediator of autoimmunity. Sustained IFNα signaling is linked to pathogenesis of systemic lupus erythematosus (SLE), an incurable autoimmune disease characterized by aberrant self-DNA sensing that culminates in anti-DNA autoantibody-mediated pathology. IFNα instructs monocytes differentiation into autoinflammatory dendritic cells (DCs) than potentiates the survival and expansion of autoreactive lymphocytes, but the molecular mechanism bridging sterile IFNα-danger alarm with adaptive response against self-DNA remains elusive. Herein, we demonstrate IFNα-mediated deregulation of mitochondrial metabolism and impairment of autophagic degradation, leading to cytosolic accumulation of mtDNA that is sensed via stimulator of interferon genes (STING) to promote induction of autoinflammatory DCs. Identification of mtDNA as a cell-autonomous enhancer of IFNα signaling underlines the significance of efficient mitochondrial recycling in the maintenance of peripheral tolerance. Antioxidant treatment and metabolic rescue of autolysosomal degradation emerge as drug targets in SLE and other IFNα-related pathologies.
干扰素 α（IFNα）是宿主防御核酸的快速而有效的协调者，但在慢性期成为自身免疫的有力介质。持续的 IFNα 信号与系统性红斑狼疮（SLE）的发病机制有关，SLE 是一种无法治愈的自身免疫性疾病，其特征是异常的自身 DNA 感应，最终导致抗 DNA 自身抗体介导的病理学。IFNα 指示单核细胞分化为自身炎症树突状细胞（DCs），从而增强了自身反应性淋巴细胞的存活和扩增，但将无菌 IFNα-危险警报与针对自身 DNA 的适应性反应联系起来的分子机制仍然难以捉摸。本文中，我们证明了 IFNα 介导的线粒体代谢失调和自噬降解受损，导致线粒体 DNA 在细胞质中的积累，通过干扰素基因刺激物（STING）来促进自身炎症性 DCs 的诱导。鉴定 mtDNA 作为 IFNα 信号的细胞自主增强子，强调了有效的线粒体回收在维持外周耐受中的重要性。抗氧化剂治疗和自溶酶体降解的代谢挽救作为 SLE 和其他 IFNα 相关病理的药物靶点出现。
