The oxidized phospholipid oxPAPC ameliorates septic shock by targeting the non-canonical inflammasome in macrophages
Bibliographic record
Abstract
Abstract Inflammasomes are signaling complexes that link the recognition of pathogen and danger associated molecular patterns (PAMPs and DAMPs) by cytosolic pattern-recognition receptors (PPRs) to the activation of Caspase-1, leading to the release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18, and the induction of pyroptosis. In addition to the canonical inflammasome activation by Caspase-1, other inflammatory caspases including murine Caspase-11 and its human orthologs Caspase-4 and Caspase-5 participate in the non-canonical pathway in response to intracellular LPS and Gram negative bacteria escaping the phagosomes, resulting in pyroptotic cell death as well as NLRP3 inflammasome-dependent cytokine release. Contrary to the highly regulated multiprotein platform required for Caspase-1 activation in the canonical inflammasomes, non-canonical inflammatory caspases are directly activated by binding to LPS thus simultaneously act as innate sensors and effectors. It is still largely unknown how the activity of these caspases is regulated. Here we identified the oxidized phospholipid 1-Palmitoyl-2-arachidonoyl-sn- glycero-3-phosphorylcholine (oxPAPC) as a negative regulator of the non-canonical inflammasome in macrophages. In addition to its previously reported TLR4 antagonistic role, oxPAPC directly binds to Caspase-4 and Caspase-11, competes with LPS binding and consequently, inhibits LPS-induced pyroptosis, IL-1β release and septic shock in vivo. Therefore, oxPAPC and its derivatives could provide a basis for novel therapies targeting non-canonical inflammasomes during Gram-negative bacterial sepsis.
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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 | 0.001 |
| 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".