Abstract 107: The Innate Immune NALP3 Receptor Mediates Cardiac Ischemic Preconditioning in the Isolated Heart
Bibliographic record
Abstract
Objective: Recent studies indicate that the innate immune system is not only activated by exogenous pathogens and pollutants, but also by endogenous danger signals released during ischemia and necrosis. As activation triggers (cellular K+ extrusion, ROS production) for the innate immune NALP3 inflammasome protein complex overlap with those for cardiac ischemia-reperfusion (I/R) and ischemic preconditioning (IPC), we explored the possibility that the NALP3 inflammasome is involved in IPC and acute I/R injury of the heart. Methods & Results: Baseline performance and I/R injury was investigated in isolated, Langendorff-perfused hearts from wild-type, ASC-/- and NALP3-/- mice. Baseline cardiac performance was unaffected by genetic deletion of NALP3 inflammasome components. Deletion of the ASC and NALP3 component exacerbated IR injury on mechanical parameters of the heart. However, deficiency in ASC or NALP3 was without effect on cell death (LDH release during reperfusion). In a separate series we subjected these same hearts to IPC, consisting of 3 x 5 min I/R preceding the 35 min I. IPC protected WT and ASC-/- hearts against IR injury (improved function and less cell death). However, no IPC effects on function or cell death were observed in NALP3-/- hearts. NALP3-/- hearts had significantly decreased cardiac IL-6 levels with a trend towards lower Il-1β levels at end reperfusion, suggesting abrogating of IPC through diminished IL-6 and/or Il-1β signalling. However, subsequent experiments showed that inhibition of the IL-1r receptor with the IL-1 receptor inhibitor Anakinra (100 mg/L) was without effect on IPC in WT hearts. In contrast, neutralising IL-6 using an antibody against IL-6 in WT hearts abrogated IPC in NALP3-/- hearts. Conclusions: The data suggest that the innate immune NALP3 protein, in an NALP3-inflammasome-independent fashion, is an integral component of IPC in the isolated heart, possibly through an IL-6 dependent mechanism
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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 | 0.006 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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 | 0.001 |
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 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".