Abstract 383: MLKL (Mixed Lineage Kinase Domain-like Protein) In The Splenic Microenvironment Restrains Hematopoietic Contributions To The Atherosclerotic Plaque
Bibliographic record
Abstract
The mixed lineage kinase domain-like protein (MLKL) was first discovered in 2012 as the executioner of necroptosis. In line with this, we showed that MLKL knockdown ( Mlkl KD) by administration of antisense oligonucleotides to atherosclerotic-prone Apoe -knockout ( Apoe -/-) mice did indeed decrease necroptosis and necrotic core in the atherosclerotic plaque. However, there were no changes in overall plaque area, suggesting additional roles of MLKL during atherosclerosis. During atherogenesis, the spleen allows for the expansion of hematopoietic stem and progenitor cells (HSPCs) and mature myeloid cells that drive atherogenesis. Accordingly, we observed splenomegaly with an expansion of splenic HSPCs and mature myeloid cells upon Mlkl KD. However, bone marrow transplantation studies revealed that MLKL did not impact hematopoiesis through its expression in hematopoietic cells. Within hematopoietic reservoirs such as the spleen, HSPCs are regulated by their interaction with microenvironmental cell types, including endothelial cells. We thus hypothesized that MLKL preserves the microenvironment to repress hematopoiesis in the spleen during atherosclerosis. Flow cytometry and immunofluorescence staining during a time course of atherosclerosis revealed a progressive decrease of splenic endothelial cells that was correlated with a reduction of MLKL endogenously or by Mlkl KD, suggesting that splenic MLKL modulates the endothelial cells known to regulate hematopoiesis. RNA sequencing of these splenic endothelial cells revealed two major pathways that were perturbed upon Mlkl KD, including cell cycle and factors related to leukocyte differentiation. Adoptive transfer of CD45.1 HSPCs to CD45.2 Apoe -/- mice during Mlkl KD revealed an expansion of mature immune cells in the spleen as compared to control, together demonstrating the influence of MLKL on the splenic microenvironment and subsequently hematopoiesis. In conclusion, we here demonstrate a novel role for MLKL in regulating the balance of hematopoiesis, specifically through preservation of splenic endothelial cells that promote HSPC quiescence, and more generally highlight the contributions of the spleen and its impact on inflammatory pathways that potentiate 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".