Apoptotic cell induced, TLR9-dependent AhR activity is a critical driver of tolerance induction and suppression of lupus
Bibliographic record
Abstract
Abstract The Aryl hydrocarbon receptor (AhR) can potently modulate immunity at multiple levels, but its mechanistic role in immune regulation is still being elucidated. Here we show phagocytes exposed to apoptotic cells exhibit rapid activation of AhR driving IL-10 that antagonizes inflammatory cytokine production. AhR activation was dependent on apoptotic cell DNA-TLR9 interactions and reactive oxygen species (ROS) production in phagocytes that promoted nuclear accumulation and transcriptional activity. In vivo, apoptotic cell-induced AhR signals in myeloid cells were required for prevention of inflammatory innate and adaptive immunity against DNA and histones. Moreover, disease progression in lupus correlated with AhR signal strength, and disease course could be reduced or exacerbated by modulation of AhR activity. Finally, we observed myeloid specific deletion of AhR in mice resulted in systemic autoimmunity, and in SLE patients an increased AhR transcriptional signature correlated with disease. Thus, our findings suggest AhR activity influenced by apoptotic cell death is a key mechanism in maintenance of peripheral tolerance reducing inflammation and thereby retarding systemic autoimmune disease progression.
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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) | 0.002 | 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".