Mitochondrial ROS and base excision repair steps leading to DNA nick formation drive ultraviolet induced-NETosis
Bibliographic record
Abstract
Reactive oxygen species (ROS) is essential for neutrophil extracellular trap formation (NETosis), and generated either by NADPH oxidases (e.g., during infections) or mitochondria (e.g., sterile injury) in neutrophils. We recently showed that ultraviolet (UV) radiation, a sterile injury-inducing agent, dose-dependently induced mitochondrial ROS generation, and increasing levels of ROS shifted the neutrophil death from apoptosis to NETosis. Nevertheless, how ROS executes UV-induced NETosis is unknown. In this study, we first confirmed that UV doses used in our experiments generated mitochondrial ROS, and the inhibition of mitochondrial ROS suppressed NETosis (Mitosox, SYTOX, immunocytochemistry, imaging). Next, we showed that UV irradiation extensively oxidized DNA, by confocal imaging of 8-oxyguanine (8-oxoG) in NETs. Immunofluorescence microscopy further showed that a DNA repair protein, proliferating cell nuclear antigen, was widely distributed throughout the DNA, indicating that the DNA repair machinery was active throughout the genome during UV-induced NETosis. Inhibition of specific steps of base excision repair (BER) pathway showed that steps leading up to DNA nick formation, but not the later steps, suppressed UV-induced NETosis. In summary, this study shows that (i) high levels of mitochondrial ROS produced following UV irradiation induces extensive oxidative DNA damage, and (ii) early steps of the BER pathway leading to DNA nicking results in chromatin decondensation and NETosis. Collectively, these findings reveal how ROS induces NOX-independent NETosis, and also a novel biological mechanism for UV irradiation- and -mitochondrial ROS-mediated NETosis.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".