Macrophage NOX2 NADPH oxidase maintains alveolar homeostasis in mice
Bibliographic record
Abstract
The leukocyte NADPH oxidase 2 (NOX2) plays a key role in pathogen killing and immunoregulation. Genetic defects in NOX2 result in chronic granulomatous disease (CGD), associated with microbial infections and inflammatory disorders, often involving the lung. Alveolar macrophages (AMs) are the predominant immune cell in the airways at steady state, and limiting their activation is important, given the constant exposure to inhaled materials, yet the importance of NOX2 in this process is not well understood. In this study, we showed a previously undescribed role for NOX2 in maintaining lung homeostasis by suppressing AM activation, in CGD mice or mice with selective loss of NOX2 preferentially in macrophages. AMs lacking NOX2 had increased cytokine responses to Toll-like receptor-2 (TLR2) and TLR4 stimulation ex vivo. Moreover, between 4 and 12 week of age, mice with global NOX2 deletion developed an activated CD11bhigh subset of AMs with epigenetic and transcriptional profiles reflecting immune activation compared with WT AMs. The presence of CD11bhigh AMs in CGD mice correlated with an increased number of alveolar neutrophils and proinflammatory cytokines at steady state and increased lung inflammation after insults. Moreover, deletion of NOX2 preferentially in macrophages was sufficient for mice to develop an activated CD11bhigh AM subset and accompanying proinflammatory sequelae. In addition, we showed that the altered resident macrophage transcriptional profile in the absence of NOX2 is tissue specific, as those changes were not seen in resident peritoneal macrophages. Thus, these data demonstrate that the absence of NOX2 in alveolar macrophages leads to their proinflammatory remodeling and dysregulates alveolar homeostasis.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.002 |
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".