Abstract MP09: MLKL (Mixed Lineage Kinase Domain-like Protein) Is A Novel Regulator Of The Splenic Microenvironment That Restricts Hematopoiesis During Atherosclerosis
Bibliographic record
Abstract
During atherosclerosis, macrophages within the aorta undergo necroptosis, a mode of pro-inflammatory cell death that is triggered by the phosphorylation of RIPK1 & RIPK3 and leads to the activation of the mixed lineage kinase domain-like protein (MLKL) and cell lysis. Our previous work demonstrated that while inhibition of MLKL decreased necroptosis and necrotic core in the plaque, unlike RIPK1 & RIPK3 this inhibition did not lead to overall decrease in plaque area, suggesting that MLKL may in fact participate in other processes that drive atherosclerotic plaque development. Because circulating leukocytes are recruited and contribute to the growing atheroma, and these leukocytes are derived from hematopoietic stem and progenitor cells (HSPCs) found in both the bone marrow (BM) and the spleen, we investigated whether these hematopoietic reservoirs became dysregulated upon loss of MLKL during atherogenesis. To induce atherogenesis, Apoe -knockout mice ( Apoe -/-) were fed a high fat-high cholesterol diet for 16 weeks while receiving weekly subcutaneous administration of antisense oligonucleotides (ASOs) to knockdown MLKL expression. In the Apoe -/- mice receiving MLKL ASO we observed a 3.1-fold increase in splenomegaly compared to the control ASO, specifically with an expansion of the splenic red pulp, the area of splenic hematopoiesis. Furthermore, flow cytometry revealed a significant increase in myeloid HSPCs and mature myeloid populations in the spleen, but not the BM, after MLKL knockdown. However, no changes were observed in these hematopoietic measures after transplantation of Ldlr -knockout mice with MLKL-knockout BM, indicating that MLKL restricts hematopoiesis through its regulation of non-hematopoietic cells of the splenic niche. Indeed, upon MLKL knockdown in the Apoe -/- mice we observed a >50% reduction in splenic endothelial cells, which are required to promote HSPC quiescence and repress hematopoiesis. These data therefore demonstrate a novel role for MLKL on preserving splenic endothelial cells to limit immune cell development during atherosclerosis, and more generally, highlight the importance of the dysregulation of the splenic microenvironment to contributing to the inflammatory processes that drive atherosclerosis.
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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 | 0.001 |
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".