GSDMD pore formation regulates caspase-4 cleavage to limit IL-18 production in the intestinal epithelium
Bibliographic record
Abstract
Abstract Epithelial inflammasomes induce pyroptosis and release cytokines to defend against cytosolic pathogens. However, pyroptosis in epithelial barriers must be carefully regulated to facilitate elimination of infected cells while limiting widespread pyroptosis to preserve the single cell barrier. How epithelial cells achieve this is unknown. In this study, we describe a novel epithelial caspase regulation mechanism. By examining caspase-4 activation in human epithelial cells, we discovered that GSDMD pore formation serves as a signal to terminate caspase-4 activity thus facilitating epithelial cell expulsion while controlling cytokine secretion. Inhibition of epithelial pyroptosis led to IL-18 hyperproduction, likely as a mechanism to combat increased pathogen burden and initiate a wider immune response. Moreover, we demonstrate that full-length, rather than cleaved caspase-4 is active against IL-18 and propose that GSDMD pore formation facilitates cleavage of caspase-4 to terminate its catalytic activity. By comparing human cells and murine epithelial organoids to immune cells, we show that GSDMD pore mediated inhibition of caspase activity is largely specific to epithelial cells. Overall, these studies characterise a novel, epithelial-specific negative feedback loop that modulates inflammasome activity and challenge the dogma that autocatalytic caspase cleavage is required for caspase activity against substrates. Graphical Abstract In intestinal epithelial cells, caspase activation simultaneously leads to GSDMD pore formation and IL-18 release. GSDMD pore formation provides a signal to terminate caspase activity and limit cytokine production. In GSDMD deficient cells, lack of an inhibition signal leads to caspase mediated IL-18 hyperproduction. Upon cell death this leads to release of massive amounts of IL-18. Created with BioRender.com
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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) | 0.004 | 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".