NLRP3 Inflammasome is terminated by PGE <sup>2</sup> ‐cAMP‐PKA signaling
Bibliographic record
Abstract
Inflammatory responses are measured and tightly controlled. Inflammasome activation has emerged as a major pathway of inflammation: these are intracellular complexes activated by pathogens and cellular stresses that recruit and activate caspase‐1, which successively activates IL‐1β. To date, we know little on how inflammasome activation is terminated. Macrophages highly express inflammasomes and are primary producers of IL‐1β. PGE 2 is a potent lipid mediator liberally produced at sites of inflammation and can alter many innate immune functions of macrophages. Here we show NLRP3 inflammasome is rapidly dampened by concurrent PGE 2 ‐cAMP‐PKA signaling. Bonemarrow‐ derived or THP‐1 macrophages were stimulated with LPS followed by nigericin or ATP to activate the NLRP3 inflammasome. Caspase‐1 and IL‐1β activation were detected by Western blot and ELISA. Co‐application of PGE 2 or highly selective EP2 and EP4 agonists diminished NLRP3 activation. NLRP3 inhibition was reproduced by the cAMP agonist forskolin, cAMP analogue db‐cAMP and selective PKA activation. Likewise, PKA inhibition reversed NLRP3 inhibition by PGE 2 and agonists of EP2, EP4 and cAMP. This is the first study to show PGE 2 signaling arrests activation of the NLRP3 inflammasome. This work is funded by NSERC.
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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 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".