CNS Inflammasome Activation and Modulation in Multiple Sclerosis (P5.333)
Bibliographic record
Abstract
Objective: To investigate inflammasome activation and regulation in the central nervous system (CNS) during multiple sclerosis (MS). Background: Inflammasomes are multi-protein signaling platforms that mediate proteolytic maturation of pro-inflammatory cytokines (IL-1β and -18) by caspase-1 and -4. Initially identified in peripheral myeloid cells, inflammasomes have been identified in microglia, astrocytes, and neurons but their contributions to MS pathogenesis remain unknown. Methods: Cultured primary human microglia, astrocytes and neurons were activated by inflammasome-associated stimuli with measurement of IL-1β by ELISA. Using qRT-PCR and neuropathological tools, individual inflammasome genes were analyzed in cerebral white matter samples from MS and non-MS (control) patients and in the CNS from MOG/CFA-induced experimental autoimmune encephalomyelitis (MOG-EAE) in C57Bl6 female mice. To modulate inflammasome expression, MOG-EAE mice were treated daily intraperitoneally with the caspase-1/4 inhibitor, VX-765 or vehicle. Results: Activation of microglia, and to a lesser extent astrocytes, by lipopolysaccharide (LPS), ATP and nigericin caused IL-1β release, unlike neurons. Inflammasome-associated genes (caspase-1, caspase-4, IL-1β, and the scaffold protein ASC) showed higher transcript levels in white matter of MS (n=15) compared to non-MS patients (n=12) (p<0.05). IL-1β, NLRP3 and caspase-1 p10 immunoreactivity in macrophages/microglia was detected within demyelinated MS lesions. Additionally, NLRP3, NLRP1, AIM2, and pyrin transcript levels were induced in MS compared to non-MS white matter (p<0.05). In MOG-EAE, NLRP3, NLRP1, NLRC4, NLRP12, AIM2, ASC, caspase-4/11 and IL-1β were induced sequentially over the course of disease compared to CFA-exposed (control) animals (p<0.05). Increased IL-1β and caspase-1 immunoreactivity was evident in spinal cords at peak disease in areas of demyelination while VX-765 treatment suppressed the severity of EAE (p<0.05). Conclusions: Multiple inflammasome genes were activated in both MS and EAE, principally in CNS macrophages/microglia. Inflammasome modulation by a capsase-1/4 inhibitor was protective in MOG-EAE. Understanding the pathogenic contributions of individual inflammasomes might unveil novel therapeutic targets in MS.
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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 | 0.000 |
| 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".