IRG1/Itaconate axis-mediated inter-organ communication: unraveling bone marrow dynamics in pulmonary hypertension
Bibliographic record
Abstract
Pulmonary hypertension (PH) is a fatal cardiopulmonary disorder characterized by pulmonary vascular remodeling and right ventricular hypertrophy, in which bone marrow (BM)-derived myeloid cells play a significant role. Immune-Responsive Gene 1 (IRG1) drives itaconate production in pro-inflammatory macrophages; however, its role in PH remains unclear. Our data reveal that IRG1 is upregulated in BM samples from PH patients. Irg1−/− mice exhibit baseline pulmonary vascular remodeling and cardiac hypertrophy, which worsen under hypoxia, alongside robust infiltration of macrophages and dendritic cells into the lung and heart. Adoptive transfer of Irg1-deficient BM induces cardiac hypertrophy in wild-type recipients, implicating hematopoietic progenitors in PH pathogenesis. Irg1−/− mice show reduced long-term hematopoietic stem cells (HSCs) and an expansion of lymphoid-primed multipotent progenitors, with pronounced enrichment of immunometabolic pathways, including NLRP3 inflammasome and complement system, along with dysregulation of purine metabolism. Notably, 4-octyl-itaconate (4-OI) reduces vascular cell proliferation from PH patients in vitro and attenuates monocrotaline-induced PH in rats. In conclusion, our findings indicate that IRG1/itaconate axis deficiency drives cardiopulmonary pathology by dysregulating HSC differentiation and mobilization through immunometabolic alterations, ultimately leading to pulmonary vascular remodeling and cardiac hypertrophy. PH progression could be mitigated through itaconate administration, highlighting its potential as a therapeutic strategy for PH and related cardiac complications.
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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".