Unknown,Transcriptomics,Genomics,Proteomics

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

ABSTRACT: 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 residues. When MtDNA undergoes oxidation, it is directly routed to lysosomes for degradation. This rerouting requires dissociation from the transcription factor 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 IFNprimed neutrophils, to anti-RNP autoantibodies blocks TFAM phosphorylation, a necessary step for nucleoid dissociation. Consequently, oxidized 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 oxidized nucleoids is a feature of SLE blood neutrophils, and autoantibodies against oxidized mtDNA are present in a fraction of patients. This pathway represents a novel therapeutic target in human SLE. 4 samples, no replicates, 2 controls. 2 samples are Neutrophils cultured with and without CCCP (control). 2 samples are Monocytes cultured with and without CCCP (control).

ORGANISM(S): Homo sapiens

SUBMITTER: Nicole Baldwin

PROVIDER: E-GEOD-78243 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The goal of this analysis was to utilize microarray profiling to identify basal alterations in gene expression in response to TFAM depletion and mtDNA stress. Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein, TFAM (transcription factor A,mitochondrial), regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)–IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signaling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity. Murine embryonic fibroblasts were isolated from wild-type or Tfam+/- E13.5 littermate embryos. RNA from passage-matched wild-type and Tfam+/- MEF lines was extracted in duplicate and hybridized onto Affymetrix microarrays. Four arrays were performed in total with two technical replicates per genotype.

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

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