MiR-223 Enhances Lipophagy by Suppressing CTSB in Microglia Following Lysolecithin-Induced Demyelination in Mice
Bibliographic record
Abstract
Abstract Background Lipid droplet (LD)-laden microglia are key pathological hallmarks of multiple sclerosis. The recent discovery of a novel microglial subtype, lipid-droplet-accumulating microglia (LDAM), is notable for increased inflammatory factor secretion and diminished phagocytic capability. Lipophagy, the autophagy-mediated selective degradation of LDs, plays a critical role in this context. This study investigates microRNA (miRNA) involvement in lipophagy during demyelinating diseases, assesses their capacity to modulate LDAM subtypes, and elucidates potential underlying mechanisms. Methods We conducted in vivo experiments using C57BL/6 mice. Two weeks post-demyelination induction at the cervical level 4 (C4), we performed histological assessments and confocal imaging to examine LD accumulation in microglia within the lesion site. Autophagic changes were observed using transmission electron microscopy. MiRNA and mRNA multi-omics analyses identified differentially expressed miRNAs and mRNAs under demyelinating conditions and the related autophagy target genes. We specifically explored the role of miR-223 in lipophagy in these conditions. In vitro studies, including miR-223 upregulation in BV2 cells via lentiviral transfection, validated bioinformatics findings. Immunofluorescence staining measured LD accumulation, autophagy levels, target gene expression, and inflammatory mediators, elucidating miR-223's mechanisms in LDAM. Results Oil Red O staining and confocal imaging revealed substantial LD accumulation in the demyelinated spinal cord. Transmission electron microscopy showed increased autophagic vacuoles at the injury site. Multi-omics analysis pinpointed miR-223 as a crucial regulatory gene in lipophagy during demyelination. Integrating miRNA, mRNA, and autophagy gene databases identified Cathepsin B (CTSB) as a miR-223 target in autophagy. In vitro, miR-223 upregulation suppressed CTSB expression in BV2 cells, augmented autophagy, alleviated LD accumulation, and decreased IL-1β, an inflammatory mediator. Conclusion These findings indicate miR-223's pivotal role in lipophagy during demyelinating conditions. By inhibiting CTSB, miR-223 promotes selective LD degradation, thereby reducing the lipid burden and inflammatory phenotype in LDAM. This study broadens our understanding of lipophagy's molecular mechanisms and proposes lipophagy induction as a potential therapeutic approach to mitigate inflammatory responses in demyelinating diseases.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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; 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".