Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease
Open accessAbstract
Neutrophil extracellular traps (NETs) are implicated in autoimmunity, but how they are generated and their roles in sterile inflammation remain unclear. Ribonucleoprotein immune complexes (RNP ICs), inducers of NETosis, require mitochondrial reactive oxygen species (ROS) for maximal NET stimulation. After RNP IC stimulation of neutrophils, mitochondria become hypopolarized and translocate to the cell surface. Extracellular release of oxidized mitochondrial DNA is proinflammatory in vitro, and when this DNA is injected into mice, it stimulates type I interferon (IFN) signaling through a pathway dependent on the DNA sensor STING. Mitochondrial ROS are also necessary for spontaneous NETosis of low-density granulocytes from individuals with systemic lupus erythematosus. This was also observed in individuals with chronic granulomatous disease, who lack NADPH oxidase activity but still develop autoimmunity and type I IFN signatures. Mitochondrial ROS inhibition in vivo reduces disease severity and type I IFN responses in a mouse model of lupus. Together, these findings highlight a role for mitochondria in the generation not only of NETs but also of pro-inflammatory oxidized mitochondrial DNA in autoimmune diseases.
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Mitochondrial reactive oxygen species contribute to inflammatory responses and antimicrobial activities.
“mitochondrial reactive oxygen species (mtROS)56, known to contribute to inflammatory responses and antimicrobial activities57–59”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [57]
The Results section ('RNP IC-mediated NETosis is dependent on mitochondrial ROS') links mitochondrial ROS to neutrophil extracellular trap formation, and the Discussion links it to autoimmune inflammation. The passages do not establish that mitochondrial ROS contribute to antimicrobial activity; the paper’s mention of pathogen-induced traps does not make that specific connection. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn neutrophils activated by immune complexes containing U1 snRNPs, mitochondria produce excessive ROS that supports NET formation and extrusion.
“Mechanistically, in neutrophils activated by immune complexes containing U1 small nuclear ribonucleoproteins (SnRNPs), mitochondria generate excessive amounts of ROS, which supports the formation and extrusion of NETs”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [57]
The Results section on RNP immune complex–mediated NETosis reports increased mitochondrial ROS after neutrophil activation and shows that inhibiting mitochondrial activity reduces NET formation. The Online methods describe the complexes as containing SmRNP antigen and anti-RNP antibodies, but our copy does not identify the antigen specifically as U1 snRNP. No page numbers are available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredExtruded mitochondrial components contain highly oxidized mtDNA that can provoke cGAS-STING-dependent type I interferon production, probably conserved across cell types.
“The extruded mitochondrial components contain highly oxidized mtDNA that can provoke type I interferon production in a cGAS–STING-dependent manner, a process probably well conserved among all cell types given the ubiquity of these molecules.”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [57]
The Results (‘RNP ICs induce oxidized mtDNA release’ and ‘NET-bound oxidized mtDNA is pro-inflammatory’; page not provided) report release of oxidized mtDNA and STING-dependent interferon-related responses. They do not establish that the response is conserved across all cell types: oxidized mtDNA stimulated PBMCs and THP1 cells but did not activate neutrophils despite being internalized. (LLM, conf=0.87)
Experimental — accuracy not yet measuredDifferent cellular lineages may extrude their mitochondria upon activation.
“Different cellular lineages (10–18) may extrude their mitochondria upon activation.”
From Autoantibodies in Systemic Lupus Erythematosus Target Mitochondrial RNA (2019) · cites this paper as [11]
In Results (‘RNP ICs induce oxidized mtDNA release’; page unavailable), the paper says damaged mitochondria can undergo extrusion and reports that activated neutrophils mobilize mitochondria to the cell surface and release oxidized mitochondrial DNA. It does not establish that different cellular lineages extrude whole mitochondria upon activation. (LLM, conf=0.84)
Experimental — accuracy not yet measuredExtracellular mitochondria have been identified in damaged tissues, diverse inflammatory conditions, and in the blood of critical care patients.
“Extracellular mitochondria have been identified in damaged tissues (8, 18–20); diverse inflammatory conditions (11, 12, 14, 21–24); and in the blood of critical care patients (22).”
From Autoantibodies in Systemic Lupus Erythematosus Target Mitochondrial RNA (2019) · cites this paper as [11]
The Results sections on SLE and CGD report extracellular NETs enriched in mitochondrial DNA in these inflammatory diseases. They do not establish that intact extracellular mitochondria were identified; the paper describes release of oxidized mitochondrial DNA instead. This citation is attached to the inflammatory-conditions clause, not the claims about damaged tissues or critical-care patients. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Extracellular mitochondria have been described in systemic lupus erythematosus (SLE).
“Extracellular mitochondria have been described in various clinical conditions, including trauma25,26, burn injury27, cancer28, rheumatoid arthritis17,29, systemic lupus erythematosus (SLE)15,16 and transfusion adverse reactions17,18,30,31.”
From Anti-mitochondrial autoantibodies in systemic lupus erythematosus and their association with disease manifestations (2019) · cites this paper as [15]
The Results section (“Mitochondrial ROS drive pro-inflammatory NETosis in SLE LDGs”; page not provided) reports that cells from people with SLE release NETs enriched in mitochondrial DNA. Another Results section (“RNP ICs induce oxidized mtDNA release”; page not provided) describes mitochondria moving to the cell surface and releasing DNA, but does not establish that intact mitochondria are extracellular in SLE. (LLM, conf=0.88)
Experimental — accuracy not yet measuredVarious activated cells and damaged tissues release extracellular mitochondria.
“Various cellular lineages are capable of extruding their mitochondria. Activated mast cells10, T-cells11, eosinophils12, hepatocytes13, neutrophils14–16 and platelets17,18, in addition to damaged organs or tissues7,13,19,20, release extracellular mitochondria.”
From Anti-mitochondrial autoantibodies in systemic lupus erythematosus and their association with disease manifestations (2019) · cites this paper as [15]
The citation to this paper is attached to neutrophils, not the other cell types or damaged tissues in the sentence. In Results (‘RNP ICs induce oxidized mtDNA release’; page unavailable), the paper reports that activated neutrophils mobilize mitochondria to the cell surface and release oxidized mitochondrial DNA in NETs. It does not establish that they release intact extracellular mitochondria. (LLM, conf=0.86)
Experimental — accuracy not yet measuredEmerging evidence supports the liberation of mitochondria by activated cells and their potential contribution to inflammation in SLE.
“Emerging evidence supports the liberation of mitochondria by activated cells and their potential contribution to inflammation in SLE15,16.”
From Anti-mitochondrial autoantibodies in systemic lupus erythematosus and their association with disease manifestations (2019) · cites this paper as [15]
The Results (‘RNP ICs induce oxidized mtDNA release’; page not provided) show that activated neutrophils move mitochondria to the cell surface and release oxidized mitochondrial DNA. The Discussion links that DNA release to inflammation in SLE. The paper does not establish that the cells liberate intact mitochondria, as the claim states. (LLM, conf=0.83)
Experimental — accuracy not yet measuredMitochondrial reactive oxygen species are implicated in neutrophil degranulation, neutrophil extracellular trap formation and cytokine production.
“MtROS are implicated in neutrophil degranulation, neutrophil extracellular trap (NET) formation57 and the production of cytokines59”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [57]
mtDNA extrusion can occur through NET formation.
“Extrusion of mtDNA can also occur through NET formation57.”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [57]
Blocking mtDNA extrusion with a mitochondrial ROS scavenger ameliorates SLE-like disease in lupus-prone mice, implicating oxidized mtDNA as a pathogenic driver in SLE.
“Blocking mtDNA extrusion, using a mitochondrial ROS scavenger, ameliorates SLE-like disease in lupus-prone mice, implicating oxidized mtDNA as a pathogenic driver in SLE57”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [57]
SLE neutrophils, especially low-density granulocytes, have higher baseline mitochondrial ROS generation than healthy neutrophils, promoting spontaneous NET formation and extrusion of inflammatory oxidized mtDNA.
“Notably, compared with neutrophils from healthy individuals, neutrophils from patients with SLE, particularly low-density granulocytes, have high baseline levels of mitochondrial ROS generation that promotes spontaneous NET formation and the extrusion of inflammatory oxidized mtDNA57.”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [57]
Recent evidence points to involvement of mtDNA, liberated by neutrophils, in activation of STING and type-I IFN production in SLE.
“Recent evidence point to an involvement of mtDNA, liberated by neutrophils, in the activation of STING and type-I IFN production in SLE (11, 12).”
From Autoantibodies in Systemic Lupus Erythematosus Target Mitochondrial RNA (2019) · cites this paper as [11]
In SLE, neutrophils release mtDNA through ROS generation, leading to STING activation and type-I IFN production.
“In SLE, neutrophils were shown to release mtDNA through the generation of ROS, a process leading to activation of the DNA sensor stimulator of interferon genes (STING) and type-I IFN production15,16.”
From Anti-mitochondrial autoantibodies in systemic lupus erythematosus and their association with disease manifestations (2019) · cites this paper as [15]
Oxidation of mtDNA occurs during its extrusion from cells, and the oxidized form is pathogenic.
“there are reports suggesting that the oxidation of mtDNA occurs during its extrusion from cells, and that the oxidized form is pathogenic15,16.”
From Anti-mitochondrial autoantibodies in systemic lupus erythematosus and their association with disease manifestations (2019) · cites this paper as [15]
PBC patients met the 2018 PBC classification criteria.
“and PBC patients the 2018 PBC classification criteria (4).”
From Identification of Mitofusin 1 and Complement Component 1q Subcomponent Binding Protein as Mitochondrial Targets in Systemic Lupus Erythematosus (2022) · cites this paper as [4]
The Online Methods section on human samples identifies participants with CGD or SLE and healthy controls; it says SLE participants met ACR revised diagnostic criteria. Searches for PBC and the 2018 PBC classification criteria found no passage addressing whether PBC patients met those criteria. No page number was available in our copy. (LLM, conf=0.74)
Experimental — accuracy not yet measuredA considerable fraction of nucleic acids contained in NETs is of mitochondrial rather than nuclear origin.
“Several reports demonstrate that a considerable fraction of the nucleic acids contained in NETs is of mitochondrial, rather than nuclear, origin [724–728].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [728]
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Self-citation
- Authors
- Lood, C., Blanco, L. P., Purmalek, M. M., Carmona-Rivera, C., De Ravin, S. S., Smith, C. K., Malech, H. L., Ledbetter, J. A., Elkon, K. B., & Kaplan, M. J.
- Affiliations
- University of Washington (US)
- National Institutes of Health (US)
- Corresponding author
- Elkon, Keith B
- Kaplan, Mariana J
- ORCID
- Venue
- Nature Medicine
- Published
- 2016-01-18
- Volume
- 22
- Issue
- 2
- Pages
- 146-153
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4742415
- OpenAlex
- W2261479737
- Cited by
- 1,570
- References
- 60
- Citations by year
- 2026: 152 · 2025: 157 · 2024: 200 · 2023: 166 · 2022: 170 · 2021: 183 · 2020: 125 · 2019: 151 · 2018: 103 · 2017: 92 · 2016: 68
- FWCI
- 83.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99 AR999999)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- neutrophil extracellular traps, oxidized mitochondrial DNA, systemic lupus erythematosus, NETosis, mitochondrial reactive oxygen species, type I interferon signaling, STING, chronic granulomatous disease, NADPH oxidase, autoimmunity, sterile inflammation, mitochondrial translocation
- MeSH terms
- Adult, Animals, Antigen-Antibody Complex, DNA, Mitochondrial, Female, Granulomatous Disease, Chronic, Humans, Interferon Type I, Kidney, Lupus Erythematosus, Systemic, Male, Microscopy, Fluorescence, Mitochondria, Peroxidase, Neutrophils, Oxidation-Reduction, Ribonucleoproteins, Reactive Oxygen Species, Jurkat Cells, NADPH Oxidases, Immunoprecipitation, Mice, Real-Time Polymerase Chain Reaction, Extracellular Traps, In Vitro Techniques
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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