MerTK as a Functional Regulator of Anti-Inflammatory Myelin Phagocytosis by Human Myeloid Cells (P5.273)
Bibliographic record
Abstract
OBJECTIVE: To investigate the role of MerTK in regulating the inflammatory and phagocytic response of microglia and monocyte derived macrophages (MDMs) to human myelin. BACKGROUND: Myelin-laden myeloid cells are a histological hallmark of active MS lesions. These myeloid cells are comprised of brain-resident microglia and infiltrating MDMs. While both cell types phagocytose myelin the implications for disease pathogenesis are not fully elucidated. The functional properties of myeloid cells have been linked to their state of activation. MerTK is a member of the TAM receptor family and is shown to regulate activation and phagocytosis of apoptotic cells and inhibit pro-inflammatory responses of innate immune cells. Polymorphisms in the gene coding for MerTK are associated with risk for developing MS. DESIGN/METHODS: Microglia isolated from adult brain tissue and MDMs purified from peripheral blood were activated in vitro using established pro-inflammatory (M1) and anti- inflammatory (M2) cytokine protocols and exposure to TGFβ. Phagocytosis of fluorescently labeled myelin was assessed by flow cytometry. Transcriptomal profiling (Affymetrix) was performed to examine expression of molecules involved in phagocytosis. MerTK antagonists were used to study the contribution of MerTK to myelin phagocytosis and cytokine production. RESULTS: Myelin phagocytosis by microglia was increased in cells exposed to TGFβ and decreased in M1 polarized cells. MerTK expression was enhanced in TGFβ-treated cells and decreased under M1 conditions. A similar pattern was observed in MDMs, although overall phagocytic activity and MerTK expression were lower compared to microglia. Pharmacological inhibition of MerTK reduced phagocytosis of myelin coupled with increased expression of pro-inflammatory cytokines by both myeloid cell types. CONCLUSIONS: MerTK regulates myelin phagocytosis by human myeloid cells, with its expression linked to the activation state of the cell. Enhancing MerTK expression/signaling may establish an efficiently phagocytic and anti-inflammatory myeloid cell phenotype that could reduce tissue injury and favor endogenous repair.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.006 | 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; both teacher heads agree on what is shown here.
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".