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

Athale, Shruti; Domic, Bojana; Murat, Elise; Chandra, Manjari; Banchereau, Romain; Baisch, Jeanine; Phelps, Kate; Clayton, Sandra; Gong, Mei; Wright, Tracey; Punaro, Marilynn; Palucka, Karolina; Guiducci, Cristiana; Banchereau, Jacques; Pascual, Virginia

doi:10.1083/jcb.2132oia85

Cited by 62 publications

(101 citation statements)

References 27 publications

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“…MtDNA can mediate the proinflammatory response through many different mechanisms [16]. Many situations may cause mtDNA release, such as tissue injury, proinflammatory cytokine stimulation, and stress conditions [15,25,26]. In the current study, we also identified several required processes that regulate mtDNA release in DCs induced by DENV infection.…”

Section: Discussionmentioning

confidence: 71%

Infection with the dengue RNA virus activates TLR9 signaling in human dendritic cells

et al. 2018

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Toll-like receptors (TLRs) are important sensors that recognize pathogen-associated molecular patterns. Generally, TLR9 is known to recognize bacterial or viral DNA but not viral RNA and initiate an immune response. Herein, we demonstrate that infection with dengue virus (DENV), an RNA virus, activates TLR9 in human dendritic cells (DCs). DENV infection induces release of mitochondrial DNA (mtDNA) into the cytosol and activates TLR9 signaling pathways, leading to production of interferons (IFNs). The DENV-induced mtDNA release involves reactive oxygen species generation and inflammasome activation. DENV infection disrupts the association between transcription factor A mitochondria (TFAM) and mtDNA and activates the mitochondrial permeability transition pores. The side-by-side comparison of TLR9 and cyclic GMP-AMP synthase (cGAS) knockdown reveals that both cGAS and TLR9 comparably contribute to DENV-induced immune activation. The significance of TLR9 in DENV-induced immune response is also confirmed in examination with the bone marrow-derived DCs prepared from -knockout mice. Our study unravels a previously unrecognized phenomenon in which infection with an RNA virus, DENV, activates TLR9 signaling by inducing mtDNA release in human DCs.

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Section: Discussionmentioning

confidence: 71%

Infection with the dengue RNA virus activates TLR9 signaling in human dendritic cells

et al. 2018

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“…Generation of ROS is necessary for NET formation in most contexts, and we and other investigators recently demonstrated that generation of ROS, rather than NOX-2, by mitochondria is key to the oxidation of DNA and, in particular, the oxidation of mitochondrial DNA (mtDNA) (34,38). Furthermore, oxidized mtDNA was proven to be highly inflammatory through activation of the stimulator of IFN genes (STING) pathway, inducing IFNb and other inflammatory cytokines (34).…”

Section: Neutrophils and Net Formationmentioning

confidence: 99%

“…DNA:RNA hybrids that may be produced by an infection with retroviruses or that may occur in the life cycle of endogenous retroelements are degraded by RNase H2 enzymes ( Table 1). Mitochondrial DNA has recently received much attention as an agonist capable of stimulating type I IFNs and other cytokines (34,38). Since it is readily oxidized, mtDNA is less efficiently degraded by DNases such as TREX1, leading to activation of TLR-9 and a DNA sensor, cyclic GMP-AMP (cGAMP) synthase (cGAS) (34) (see further details below).…”

Section: Extra-and Intracellular Nucleases Protect Against Inflammatimentioning

confidence: 99%

“…Mitochondria are readily damaged through hyper-or hypopolarization of their membranes, as well as by generation of ROS. Damaged mitochondria are usually removed by the process of mitophagy, but neutrophils appear to be poor at mitophagy and, therefore, extrude damaged mitochondria as a way to prevent untoward damage within the cell (34,38). Mitochondria thus have an impact on immunity, because 1) their DNA is rich in CpG DNA (potential TLR-9 ligand) and can gain entry into cells through binding to Tfam (77), 2) ROS oxidizes mtDNA (potential cGAS ligand) that cannot be efficiently repaired within the organelle, 3) in mammalian cells, they are the only source of cardiolipin (antigenic target of some autoantibodies), and 4) the damaged organelle can be extruded (making it accessible to the immune system).…”

Section: Elkonmentioning

confidence: 99%

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Review: Cell Death, Nucleic Acids, and Immunity

Elkon

2018

Arthritis & Rheumatology

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Cells of the innate immune system are rigged with sensors that detect nucleic acids derived from microbes, especially viruses. It has become clear that these same sensors that respond to nucleic acids derived from damaged cells or defective intracellular processing are implicated in triggering diseases such as lupus and arthritis. The ways in which cells die and the concomitant presence of proteins and peptides that allow nucleic acids to re-enter cells profoundly influence innate immune responses. In this review, we briefly discusses different types of programmed necrosis, such as pyroptosis, necroptosis, and NETosis, and explains how nucleic acids can engage intracellular receptors and stimulate inflammation. Host protective mechanisms that include compartmentalization of receptors and nucleases as well as the consequences of nuclease deficiencies are explored. In addition, proximal and distal targets in the nucleic acid stimulation of inflammation are discussed in terms of their potential amenability to therapy for the attenuation of innate immune activation and disease pathogenesis.

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“…Thus, cytosolic mtDNA activates the DNA sensor cGAS and promotes STING-IRF3-dependent signaling (Rongvaux et al, 2014;White et al, 2014;West et al, 2015). Furthermore, neutrophils extrude interferogenic mtDNA by a process dependent in part on lysosomal activity and that occurs in the presence of a constitutive defect in mitophagy (Caielli et al, 2016), Based on the observations that OPA1 mutations cause mtDNA instability (Kim et al, 2005;Amati-Bonneau et al, 2008;Hudson et al, 2008;Yu-Wai-Man et al, 2010), we reasoned that OPA1 deficiency in a non-immune cells should not only alter mitochondrial morphology but also mitochondrial stability, and in consequence trigger immune responses. Based on this, we analyzed the impact of Opa1 loss-offunction in skeletal muscle.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency

et al. 2018

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Opa1 participates in inner mitochondrial membrane fusion and cristae morphogenesis. Here, we show that muscle-specific Opa1 ablation causes reduced muscle fiber size, dysfunctional mitochondria, enhanced Fgf21, and muscle inflammation characterized by NF-κB activation, and enhanced expression of pro-inflammatory genes. Chronic sodium salicylate treatment ameliorated muscle alterations and reduced the muscle expression of Fgf21. Muscle inflammation was an early event during the progression of the disease and occurred before macrophage infiltration, indicating that it is a primary response to Opa1 deficiency. Moreover, Opa1 repression in muscle cells also resulted in NF-κB activation and inflammation in the absence of necrosis and/or apoptosis, thereby revealing that the activation is a cell-autonomous process and independent of cell death. The effects of Opa1 deficiency on the expression NF-κB target genes and inflammation were absent upon mitochondrial DNA depletion. Under Opa1 deficiency, blockage or repression of TLR9 prevented NF-κB activation and inflammation. Taken together, our results reveal that Opa1 deficiency in muscle causes initial mitochondrial alterations that lead to TLR9 activation, and inflammation, which contributes to enhanced Fgf21 expression and to growth impairment.

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

Cited by 62 publications

References 27 publications

Infection with the dengue RNA virus activates TLR9 signaling in human dendritic cells

Infection with the dengue RNA virus activates TLR9 signaling in human dendritic cells

Review: Cell Death, Nucleic Acids, and Immunity

Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency

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