<i>Entamoeba histolytica</i> ‐Induced Activation of Caspase‐4 Regulates Gasdermin D Cleavage to Mediate IL‐1β Secretion in Macrophages
Bibliographic record
Abstract
A hallmark of Entamoeba histolytica ( Eh ) invasion in the gut is acute intestinal inflammation dominated by the secretion of pro‐inflammatory cytokines. Eh in contact with macrophages activates caspase‐1 by the recruitment of the NLRP3 inflammasome complex in a Gal‐lectin and Eh cysteine proteases 5 ( Eh CP‐A5)‐dependent manner, resulting in the maturation and secretion of interleukin (IL)‐1β and IL‐18. Although it is well‐defined that caspase‐1 activation is important in mediating the secretion of IL‐1β and IL‐18, the role caspase‐4 play in the overall pro‐inflammatory response is less identified. We have recently shown that Eh activates caspase‐1/4 in macrophage that cleaved gasdermin D (GSDMD) leading to the insertion of N‐terminal effector domain into the cell membrane, driving both pore formation and IL‐1β secretion without causing significant cell death. In this study, we interrogated the requirements and activation mechanism for Eh ‐induced caspase‐4 activation in cleaving GSDMD and in mediating bioactive IL‐1β release. Similar to caspase‐1, caspase‐4 activation was dependent on Eh Gal‐lectin and Eh CP‐A5 binding to macrophages that triggered ATP release that acted as a second signal. To determine if Eh ‐induced activation of caspase‐4 interacted with the canonical NLRP3 inflammasome to regulate GSDMD‐mediated pro‐inflammatory cytokine release, CRISPR‐Cas9 gene editing of caspase‐1, 4, ASC, and NLRP3 THP‐1 cells were utilized. Unlike caspase‐1, caspase‐4 activation in response to Eh was triggered within 10 min and was independent of ASC, NLRP3, and caspase‐1. In the absence of caspase‐1, caspase‐4 activation was significantly up regulated that enhanced the cleavage of GSDMD to induce robust IL‐1β secretion. Eh ‐induced caspase‐4 played a major role in triggering GSDMD pore formation and bioactive IL‐1β release as quantified by HEK‐Blue™ reporter cell IL‐1β assay independent of pyroptosis. This was in marked contrast to the positive control, LPS + Nigericin that induced high expression of caspase‐1, enhanced GSDMD cleavage, IL‐1β secretion, and massive pyroptosis. These results suggest that Eh induced “hyperactivated macrophages” led to caspase‐4 dependent GSDMD cleavage and IL‐1β secretion in the absence of pyroptosis important in disease pathogenesis.
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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) | 0.002 | 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".