Myeloid‐specific deletion of activating transcription factor 6 alpha increases <scp>CD11b</scp><sup>+</sup> macrophage subpopulations and aggravates lung fibrosis
Bibliographic record
Abstract
Abstract Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease of unknown etiology. The accumulation of macrophages is associated with disease pathogenesis. The unfolded protein response (UPR) has been linked to macrophage activation in pulmonary fibrosis. To date, the impact of activating transcription factor 6 alpha (ATF6α), one of the UPR mediators, on the composition and function of pulmonary macrophage subpopulations during lung injury and fibrogenesis is not fully understood. We began by examining the expression of Atf6α in IPF patients’ lung single‐cell RNA sequencing dataset, archived surgical lung specimens, and CD14 + circulating monocytes. To assess the impact of ATF6α on pulmonary macrophage composition and pro‐fibrotic function during tissue remodeling, we conducted an in vivo myeloid‐specific deletion of Atf6α . Flow cytometric assessments of pulmonary macrophages were carried out in C57BL/6 and myeloid specific ATF6α‐deficient mice in the context of bleomycin‐induced lung injury. Our results demonstrated that Atf6α mRNA was expressed in pro‐fibrotic macrophages found in the lung of a patient with IPF and in CD14 + circulating monocytes obtained from blood of a patient with IPF. After bleomycin administration, the myeloid‐specific deletion of Atf6α altered the pulmonary macrophage composition, expanding CD11b + subpopulations with dual polarized CD38 + CD206 + expressing macrophages. Compositional changes were associated with an aggravation of fibrogenesis including increased myofibroblast and collagen deposition. A further mechanistic ex vivo investigation revealed that ATF6α was required for CHOP induction and the death of bone marrow‐derived macrophages. Overall, our findings suggest a detrimental role for the ATF6α‐deficient CD11b + macrophages which had altered function during lung injury and fibrosis.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".