Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus.

TitleOxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus.
Publication TypeJournal Article
Year of Publication2016
AuthorsCaielli 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
JournalJ Exp Med
Date Published2016 05 02
KeywordsAdolescent, Autoantibodies, Child, Child, Preschool, DNA, Mitochondrial, DNA-Binding Proteins, Female, Humans, Interferon Type I, Lupus Erythematosus, Systemic, Male, Mitochondria, Mitochondrial Proteins, Neutrophils, Oxidation-Reduction, Toll-Like Receptor 7, Transcription Factors

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.

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Alternate JournalJ. Exp. Med.
PubMed ID27091841
PubMed Central IDPMC4854735
Grant ListP50 AR054083 / AR / NIAMS NIH HHS / United States
U19 AI082715 / AI / NIAID NIH HHS / United States

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