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Oxidized mitochondrial DNA sensing by plasmacytoid dendritic cells bypasses self-tolerance to trigger Tfh dependent autoantibody production [RNA-seq]

ABSTRACT: Damage associated molecular patterns (DAMP) trigger inflammation and provide co-stimulatory signals to adaptive immune cells, but whether and how recurring innate stimuli circumvent self-tolerance and initiate maladaptive autoimmunity is unknown. We explored if oxidized mitochondrial DNA (Ox-mtDNA), a DAMP released by stressed macrophages, found in higher amounts in diverse metabolic and autoimmune disorders, including systemic lupus erythematosus (SLE), initiates antibody-mediated autoimmunity. Indeed, Ox-mtDNA release induced by repetitive alum challenges elicited germinal center reactions, autoantibody production and nephropathology. These responses were recapitulated by in-vitro generated Ox-mtDNA, while non-oxidized mtDNA was non-pathogenic. Both mtDNA forms, but not nuclear DNA, were internalized by plasmacytoid dendritic cells (pDC), activated NF-kB via TLR9 and induced interferon (IFN)-I. Yet only Ox-mtDNA triggered NLRP3- and gasdermin D-dependent IL-1β secretion, eliciting autocrine production of IL-21 that together with IL-1β, but independently of IFN-I, enabled pDC to convert naïve CD4+ T cells into follicular helper cells. Highlighting Ox-mtDNA as a uniquely immunogenic DAMP that is specifically sensed by pDC and IL-1β as an orchestrator of autoantibody production, these findings explain how chronic inflammation culminates in autoimmunity and unravel new therapeutic targets applicable to SLE, the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) and related diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE264619 | GEO | 2025/04/10

REPOSITORIES: GEO

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Oxidized mitochondrial DNA sensing by plasmacytoid dendritic cells bypasses self-tolerance to trigger Tfh dependent autoantibody production [scRNA-seq]

Project description:Damage associated molecular patterns (DAMP) trigger inflammation and provide co-stimulatory signals to adaptive immune cells, but whether and how recurring innate stimuli circumvent self-tolerance and initiate maladaptive autoimmunity is unknown. We explored if oxidized mitochondrial DNA (Ox-mtDNA), a DAMP released by stressed macrophages, found in higher amounts in diverse metabolic and autoimmune disorders, including systemic lupus erythematosus (SLE), initiates antibody-mediated autoimmunity. Indeed, Ox-mtDNA release induced by repetitive alum challenges elicited germinal center reactions, autoantibody production and nephropathology. These responses were recapitulated by in-vitro generated Ox-mtDNA, while non-oxidized mtDNA was non-pathogenic. Both mtDNA forms, but not nuclear DNA, were internalized by plasmacytoid dendritic cells (pDC), activated NF-kB via TLR9 and induced interferon (IFN)-I. Yet only Ox-mtDNA triggered NLRP3- and gasdermin D-dependent IL-1β secretion, eliciting autocrine production of IL-21 that together with IL-1β, but independently of IFN-I, enabled pDC to convert naïve CD4+ T cells into follicular helper cells. Highlighting Ox-mtDNA as a uniquely immunogenic DAMP that is specifically sensed by pDC and IL-1β as an orchestrator of autoantibody production, these findings explain how chronic inflammation culminates in autoimmunity and unravel new therapeutic targets applicable to SLE, the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) and related diseases.

2025-04-10 | GSE264620 | GEO

A novel CD4+ T cell population expanded in Systemic Lupus Erythematosus (SLE) blood provides B cell help through IL10 and succinate

Project description:A better understanding of the molecular and cellular factors involved in human plasma cell differentiation will accelerate therapeutic target identification in autoantibody-mediated diseases such as Systemic Lupus Erythematosus (SLE). Here, we describe a novel CXCR3+ PD1hi CD4+ T cell ‘helper’ population expanded in blood and inflamed kidneys of SLE patients. Upon activation, these cells express IFNg and IL10 and display high levels of mitochondrial ROS (mtROS) as the result of reverse electron transfer (RET) fueled by succinate. Furthermore, T cell-derived succinate synergizes with IL10 to provide B cell help. Cells with similar phenotype and function are generated in vitro upon priming naive CD4+ T cells with oxidized mitochondrial DNA (Ox mtDNA)- activated plasmacytoid dendritic cells (pDCs) in a PD1-dependent manner. Our results provide a novel mechanism for the initiation and/or perpetuation of extrafollicular humoral responses in SLE.

2018-09-26 | GSE109843 | GEO

A novel CD4+ T cell population expanded in SLE blood provides B cell help through IL10 and succinate

Project description:A better understanding of the mechanisms involved in human plasma cell differentiation will accelerate therapeutic target identification in autoantibody-mediated diseases such as Systemic Lupus Erythematosus (SLE). Here, we describe a novel CXCR5- CXCR3+ PD1hi CD4+ T cell ‘helper’ population distinct from follicular helper T cells (Tfh) and expanded in blood and inflamed kidneys of SLE patients. Upon activation, these cells express IFNand high levels of IL10. Additionally, they accumulate high amounts of mitochondrial ROS (mtROS) as the result of reverse electron transport (RET) fueled by succinate. These cells provide potent help to B cells through the synergistic effect of IL10 and succinate. Cells with similar phenotype and function are generated in vitro upon priming naïve CD4+ T cells with oxidized mitochondrial DNA (Ox mtDNA)-activated plasmacytoid dendritic cells (pDCs) in a PD1-dependent manner. Our results provide a novel mechanism for the initiation and/or perpetuation of extrafollicular humoral responses in SLE.

2018-09-26 | GSE118951 | GEO

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

Project description: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).

2016-04-07 | E-GEOD-78243 | biostudies-arrayexpress

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

2016-04-07 | GSE78243 | GEO

RNA-Sequencing Analysis of ox-LDL-treated Peritoneal Macrophages Transcriptomes

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2021-05-19 | GSE171413 | GEO

Amino acid transport represents a druggable process for inhibiting human plasmacytoid dendritic cell activity during autoimmunity

Project description:IL-3 mediates human plasmacytoid dendritic cell (pDC) survival in vitro, but its mechanism of action is unclear. We show that, through JAK2/STAT5, IL-3 and the related GM-CSF, induce expression of System L amino acid transporters SLC7A5 and SLC3A2. This primes pDC to allow subsequent activation of mTORC1 in response to TLR9 stimulation. Active mTORC1 facilitates increased metabolic activity, type I IFN and TNF production, and the expression of SLC7A11, a subunit of the cystine/glutamate antiporter, xc—. We found that co-expression of SLC7A5, SLC3A2 and SLC7A11 is a major transcriptional signature shared by cytokine-producing pDC in vitro, and pDC at sites of autoimmune kidney damage in systemic lupus erythematosus (SLE). Targeting the expression or function of these transporters with inhibitors of JAK2 and of xc— synergistically blocked cytokine production by pDC. We propose that such an approach may have value for treating SLE, and other diseases in which pDC are implicated.

2022-04-07 | GSE157305 | GEO

Lupus Nephritis is characterized by defective removal of Neutrophil Extracellular Traps that are modified in protein composition and contain specific auto-antigens.

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2019-11-12 | PXD007754 | Pride

Gene expression in RNP autoantibody+ systemic lupus erythematosus (SLE) patient blood

Project description:The goal of this study was to characterize gene expression profiles in RNP autoantibody+ SLE versus healthy blood donors with a focus on select cytokines that may be important in B cell activation and differentiation, including BAFF, IL-21, and IL-33. We utilized Affymetrix microarrays to characterize the global program of gene expression in the SLE patients, and to identify differentially expressed genes in patients compared to healthy controls. We examined a cohort of 79 consecutive patients classified as anti-ribonuclear protein (anti-RNP)+ systemic lupus erythematosus (SLE). All patients provided RNA samples obtained after providing informed consent. There were 73 female and 6 male subjects. Disease duration ranged from 0 to 453 months with a median of 37.5 months. SLE Disease Activity Index (SLEDAI) ranged from 0 to 31 with a median of 6. mRNA from the blood of a SLE cohort (79 patients with some repeat visits for a total of 99 arrays) and 30 healthy volunteers (one array per volunteer) were analyzed.

2015-01-01 | E-GEOD-61635 | biostudies-arrayexpress

Expression data from human healthy CD133+ bone marrow EPCs

Project description:Systemic lupus erythematosus (SLE) is characterized by increased vascular risk due to premature atherosclerosis independent of traditional risk factors. We previously proposed that interferon-α plays a crucial role in premature vascular damage in SLE. IFN-α alters the balance between endothelial cell apoptosis and vascular repair mediated by endothelial progenitor cells (EPCs) and myeloid circulating angiogenic cells (CACs). Here we demonstrate that IFN-α promotes an antiangiogenic signature in SLE and control EPCs/CACs, characterized by transcriptional repression of IL-1α and β, IL-1 receptor 1 and vascular endothelial growth factor A (VEGF-A) and upregulation of IL-1 receptor antagonist (IL-1RN) and the decoy receptor IL1-R2. IL-1β promotes significant improvement in the functional capacity of lupus EPCs/CACs, therefore abrogating the deleterious effects of IFN-α. We used microarrays to analyze the effect of IFNα on peripheral blood EPCs/CACs and on bone marrow EPCs exposed to proangiogenic stimulation. Human healthy EPCs from bone marrow were isolated and cultured under proangiogenic stimulation; after IFNa incubation or not, RNA was extracted and processed for hybridization on Affymetrix microarrays.

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