Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus.
Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus.
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DOI：
10.1084/jem.20151876
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发表时间：
2016-05-02
期刊：
影响因子：
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通讯作者：
Pascual V
中科院分区：
文献类型：
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作者：
Caielli S;Athale S;Domic B;Murat E;Chandra M;Banchereau R;Baisch J;Phelps K;Clayton S;Gong M;Wright T;Punaro M;Palucka K;Guiducci C;Banchereau J;Pascual V
作为线粒体自噬的替代方法，中性粒细胞自发排出不含氧化残基（Ox）的线粒体（mt）DNA。用IFN/αRNP处理的活化的狼疮中性粒细胞或健康中性粒细胞释放与TFAM结合的ox-mtDNA，其在pDC中诱导高水平的IFN-α。针对核酸的自身抗体和过量的I型干扰素（IFN）是人类系统性红斑狼疮（SLE）的标志。我们以前报道，SLE中性粒细胞暴露于TLR 7激动剂自身抗体释放干扰素DNA，我们现在证明是线粒体起源。我们进一步表明，健康的人类中性粒细胞不完成线粒体自噬诱导线粒体损伤。相反，它们挤出线粒体组分，包括DNA（mtDNA），没有氧化（Ox）残基。当线粒体DNA发生氧化时，它直接进入溶酶体降解。这种重新路由需要从转录因子A线粒体（TFAM）解离，TFAM是一种参与线粒体基因组维持和压缩成类核的双重高迁移率族（HMG）蛋白。SLE中性粒细胞或健康的IFN致敏的中性粒细胞暴露于抗核糖核苷酸蛋白自身抗体阻断TFAM磷酸化，这是类核解离的必要步骤。因此，Ox类核在线粒体内积累，并最终作为有效的干扰复合物被挤出。支持这种现象的体内相关性，Ox类核苷酸的线粒体保留是SLE血液中性粒细胞的特征，并且在一部分患者中存在针对Ox mtDNA的自身抗体。该通路代表了人类SLE的新治疗靶点。
As an alternative to mitophagy, neutrophils spontaneously extrude mitochondrial (mt) DNA devoid of oxidized residues (Ox). Activated lupus neutrophils or healthy neutrophils treated with IFN/αRNP release ox-mtDNA bound to TFAM, which induces high levels of IFN-α in pDCs. Autoantibodies against nucleic acids and excessive type I interferon (IFN) are hallmarks of human systemic lupus erythematosus (SLE). We previously reported that SLE neutrophils exposed to TLR7 agonist autoantibodies release interferogenic DNA, which we now demonstrate to be of mitochondrial origin. We further show that healthy human neutrophils do not complete mitophagy upon induction of mitochondrial damage. Rather, they extrude mitochondrial components, including DNA (mtDNA), devoid of oxidized (Ox) residues. When mtDNA undergoes oxidation, it is directly routed to lysosomes for degradation. This rerouting requires dissociation from the transcription factor A mitochondria (TFAM), a dual high-mobility group (HMG) protein involved in maintenance and compaction of the mitochondrial genome into nucleoids. Exposure of SLE neutrophils, or healthy IFN-primed neutrophils, to antiribonucleotide protein autoantibodies blocks TFAM phosphorylation, a necessary step for nucleoid dissociation. Consequently, Ox nucleoids accumulate within mitochondria and are eventually extruded as potent interferogenic complexes. In support of the in vivo relevance of this phenomenon, mitochondrial retention of Ox nucleoids is a feature of SLE blood neutrophils, and autoantibodies against Ox mtDNA are present in a fraction of patients. This pathway represents a novel therapeutic target in human SLE.