Live or let die: Pyroptosis and inflammasome activation in glial cells during multiple sclerosis and experimental autoimmune encephalomyelitis
Bibliographic record
Abstract
Abstract Inflammasome-associated caspases mediate the maturation and release of the proinflammatory cytokines IL-1β and IL-18, and activate the pore-forming protein gasdermin-D (GSDMD). Recently, GSDMD was shown to be the primary executioner of pyroptosis, a lytic form of programmed cell death. Excessive GSDMD pore formation causes local osmotic swelling and eventual membrane lysis. Although evidence has emerged for inflammasome activation and pyroptosis in neurological diseases, the role of GSDMD in neuroinflammation remains uncharacterized. Multiple sclerosis (MS) is the prototypic inflammatory demyelinating disease of the central nervous system (CNS). We provide molecular evidence for GSDMD-mediated inflammasome activation and pyroptosis in both macrophages/microglia and, unexpectedly, in myelin-forming oligodendrocytes (ODCs) in the CNS of patients with MS and in the associated animal model, experimental autoimmune encephalomyelitis (EAE). We observe inflammasome activation, GSDMD expression, and pyroptosis in human microglia and ODCs in vitro inflammatory stimulation. Further, we demonstrate that both caspase-1 inhibition by the small molecule inhibitor VX-765 and GSDMD inhibition via siRNAs suppress pyroptosis in human microglia. VX-765 treatment of EAE animals reduced expression of inflammasome- and pyroptosis-associated proteins in the CNS, reduced neuroinflammation, prevented axonal injury, and improved neurobehavioral performance. Thus, GSDMD-mediated pyroptosis in multiple glial populations represents a previously unrecognized mechanism of inflammatory demyelination and represents a unique therapeutic opportunity for mitigating neuroinflammation.
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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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".