Involvement of Microglial Cathepsin B in Pro-Interleukin-1 Processing and Persistent Pain
Bibliographic record
Abstract
A group of proteases in the endosomal/lysosomal proteolytic system have been designated as cathepsins, which is derived from the Greek term meaning "to digest". Considering that cathepsins can irreversibly cleave peptide bonds, the primary function of cathepsins has been believed to be their "disintegration action". However, there is increasing evidence that cathepsins can also exert "modulator actions" by which substrates are activated after limited cleavage. There is substantial evidence that cathepsin B (EC 3.4.22.1), a typical cysteine lysosomal protease, is markedly upregulated in activated microglia that accumulate in pathological sites of the brain. Beyond its bulk proteolysis in the endosomal/lysosomal system, cathepsin B can be secreted from activated microglia in its mature form to induce neuronal apoptosis and degrade A peptides that accumulate in the brain. Furthermore, cathepsin B is also leaked into the cytosol, where it plays an essential role in the inflammatory response initiated by activated microglia in the brain. Recently, the leakage of cathepsin B from the lysosomes has been suggested to trigger the activation of the NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome in microglia/macrophages after phagocytosis of various molecules including fibrillar A42 and silica crystals. After activation, the NLRP3 inflammasome can mediate pro-caspase-1 activation to promote the processing and secretion of proinflammatory cytokines, such as interleukin-1 (IL-1) and IL-18. However, the precise role of leaked cathepsin B in the activation of the NLRP3 inflammasome remains to be determined. Furthermore, there is still evidence suggesting that cathepsin B is associated with the maturation of pro-IL-1 in the endosomal/lysosomal system, because cathepsin B can effectively cleave pro-caspase-1 in a cell-free system only at an acidic pH. I herein review our current understanding of the mechanism and roles of cathepsin B in the processing and secretion of IL-1 and IL-18. Further, i also discuss a possible involvement of cathepsin B in the induction of persistent pain.
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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) | 0.000 | 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 teacher head, 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".