Microglial inflammasome activation drives developmental white matter injury
Bibliographic record
Abstract
Injury to the developing brain during the perinatal period often causes hypomyelination, leading to clinical deficits for which there is an unmet therapeutic need. Dysregulation of inflammation and microglia have been implicated, yet the molecular mechanisms linking these to hypomyelination are unclear. Using human infant cerebrospinal fluid (CSF) and postmortem tissue, we found that microglial activation of the pro-inflammatory molecular complex the NLRP3 inflammasome is associated with pathology. By developing a novel mouse brain explant model of microglial inflammasome activation, we demonstrate that blocking the inflammasome rescues myelination. In human and mouse, we discovered a link between the inflammasome product IL1β and increased levels of follistatin, an endogenous inhibitor of activin-A. Follistatin treatment was sufficient to reduce myelination, whereas myelination was rescued in injured explants upon follistatin neutralization or supplementation with exogenous activin-A. Our data reveal that inflammasome activation in microglia drives hypomyelination and identifies novel therapeutic strategies to reinstate myelination following developmental injury.
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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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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; 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".