Abstract 102: Hyperlipidemia-induced Hematopoiesis is Repressed by MLKL in Endothelial Cells of the Splenic Niche
Bibliographic record
Abstract
The mixed lineage kinase domain-like protein (MLKL) is well-known for its role in the execution of necroptotic cell death. We showed that antisense oligonucleotide knockdown of MLKL ( Mlkl KD) in Apoe -knockout mice reduces plaque necrotic core, as predicted, but not total plaque area. Additionally, Mlkl KD expanded splenic hematopoietic stem and progenitor cells (HSPCs) and mature myeloid cells known to drive atherogenesis. Thus, we hypothesized that MLKL limits splenic hematopoiesis and thereby immune cell contributions to the growing atheroma. To test whether hematopoietic or non-hematopoietic MLKL expression was responsible for HSPC expansion, we transplanted Ldlr -knockout mice with Mlkl -knockout bone marrow and found no changes in hematopoiesis, suggesting that MLKL functions in other cells in the splenic niche. Flow cytometry and immunofluorescence staining during a time course of atherosclerosis revealed a decrease of splenic endothelial cells that was correlated with a reduction of MLKL endogenously or by Mlkl KD, suggesting that MLKL maintains splenic endothelial cells. Both in vivo and in vitro we observed increased lipid accumulation and concomitant defects in cell cycle in Mlkl KD splenic endothelial cells. Similar to our previous work in macrophages, Mlkl KD led to an accumulation of CHMP4B in cultured splenic endothelial cells, suggesting aberrant endocytic trafficking, which has also been linked to dysfunctional proliferation. Furthermore, there was greater production of immune cells derived from transplanted CD45.1 HSPCs in Mlkl KD recipient spleens. Co-culture with Mlkl KD splenic endothelial cells increased HSPC expression of pStat5, a marker of activation, which was coupled with an increase in myeloid colony formation, as compared to co-culture with control splenic endothelial cells. Remarkably no changes in HSPC regulation were found upon Mlkl KD in bone marrow endothelial cells. In conclusion, we demonstrate a novel role for MLKL in regulating the balance of HSPCs, specifically through preservation of splenic endothelial cells that repress hematopoiesis, highlighting the importance of spleen lipid metabolism and its impact on inflammation that potentiates atherogenesis.
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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) | 0.003 | 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".