A41 THE ROLE OF PGC-1α IN MURINE BONE MARROW DENDRITIC CELLS
Bibliographic record
Abstract
Abstract Background The intestinal immune system tolerates food antigens and the commensal microbiota to prevent chronic inflammation. Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn’s disease, are characterized by the loss of tolerance towards the microbiota, leading to inflammation, which is characterized by the high production of cytokines such as TNF and the influx of macrophages and neutrophils to the gut. Tolerance is driven by tolerogenic dendritic cells (tolDCs). Currently, there is no cure for IBD and while available treatments may reduce symptoms, there are no pharmacological therapies that specifically seek to rescue tolerance. Inducing tolDCs in patients with IBD may be a promising therapy since it is a way to directly target the main cause of the disease. tolDCs have been defined by down-regulating TNF (pro-inflammatory cytokine), producing IL-10 (anti-inflammatory cytokine), and active oxidative phosphorylation (OXPHOS) in the mitochondria. Aims Given the tolDC characteristic of active OXPHOS, the objective of our project was to evaluate the role of PGC-1α, a major mediator of mitochondria biogenesis, in generating toDCs using murine bone marrow-derived dendritic cells (BMDC). Our hypothesis is that tolDCs would be (1) generated by pharmacological activation of PGC-1α by ZLN005, and (2) constrained by inhibition of PGC-1α by SR18292. Methods We treated BMDC cultures with ZLN005 (PGC-1α activator) or SR18292 (PGC-1α inhibitor), and LPS. We characterized the effect of PGC-1α manipulation on the metabolism of BMDCs by metabolomics and Seahorse XF Cell Mito Stress Test. In addition, we evaluated features of tolDCs, such as gene expression by qPCR, and cytokine production by ELISA. Results We observed that activation of PGC-1α altered the metabolic profile of BMDC, and upregulates genes known to be expressed in tolDCs. However, this transcriptional upregulation was lost after LPS stimulation and did not alter TNF or IL-10 levels in BMDCs. PGC-1α inhibition, on other hand, decreased features of tolDCs, such as metabolic profile, transcriptional activation, and the levels of LPS-induced IL-10. Our data suggest that PGC-1α activation with ZLN005 does not increase the generation of tolDCs in vitro. However, inhibition of PGC-1α with SR18292 constrains tolDCs generation. Conclusions PGC-1α is important for the development of tolDCs in murine dendritic cells. Funding Agencies NSERC and FRQNT
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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 | 0.001 |
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".