The Nlrp3 inflammasome promotes myocardial dysfunction in structural cardiomyopathy through interleukin‐1β
Bibliographic record
Abstract
New findings What is the central question of this study? Heart failure is associated with persistent sterile inflammation that worsens disease severity; however, the molecular mechanisms behind cytokine recruitment and their relevance in the diseased myocardium remain unknown. What is the main finding and its importance? We show that interleukin‐1β is activated downstream of the Nlrp3 inflammasome in calcineurin‐transgene‐induced structural heart disease. Genetic deletion of Nlrp3 abrogated inflammasome signalling and interleukin‐1β release, improving function. The role of Nlrp3 in non‐ischaemic cardiomyopathy and the utility of inflammasome antagonism have not yet been explored, revealing potential for translational application. Heart failure is associated with a low‐grade and chronic cardiac inflammation that impairs function; however, the mechanisms by which this sterile inflammation occurs in structural heart disease remain poorly defined. Cardiac‐specific heterozygous overexpression of the calcineurin transgene (CNTg) in mice results in cardiac hypertrophy, inflammation, apoptosis and ventricular dilatation. We hypothesized that activation of the Nlrp3 inflammasome, an intracellular danger‐sensing pathway required for processing the pro‐inflammatory cytokine interleukin‐1β (IL‐1β), may contribute to myocardial dysfunction and disease progression. Here we report that Nlrp3 mRNA was increased in CNTg mice compared with wild‐type. Consistent with inflammasome activation, CNTg animals had increased conversion of pro‐caspase‐1 to cleaved and activated forms, as well as markedly increased serum IL‐1β. Blockade of IL‐1β signalling via chronic IL‐1 receptor antagonist therapy reduced cardiac inflammation and myocyte pathology in CNTg mice, resulting in improved systolic performance. Furthermore, genetic ablation of Nlrp3 in CNTg mice reduced pro‐inflammatory cytokine maturation and cardiac inflammation, as well as improving systolic performance. These findings indicate that activation of the Nlrp3 inflammasome in CNTg mice promotes myocardial inflammation and systolic dysfunction through the production of pro‐inflammatory IL‐1β. Blockade of IL‐1β signalling with the IL‐1 receptor antagonist reverses these phenotypes and offers a possible therapeutic approach in the management of heart failure.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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".