Stat2 loss disrupts damage signalling and is protective in acute pancreatitis
Bibliographic record
Abstract
Abstract The severity of sterile inflammation, as seen in acute pancreatitis, is determined by damage‐sensing receptors, signalling cascades and cytokine production. Stat2 is a type I interferon signalling mediator that also has interferon‐independent roles in murine lipopolysaccharide‐induced NF‐κB‐mediated sepsis. However, its role in sterile inflammation is unknown. We hypothesised that Stat2 determines the severity of non‐infective inflammation in the pancreas. Wild type (WT) and Stat2 −/− mice were injected i.p. with caerulein or l ‐arginine. Specific cytokine‐blocking antibodies were used in some experiments. Pancreata and blood were harvested 1 and 24 h after the final dose of caerulein and up to 96 h post l ‐arginine. Whole‐tissue phosphoproteomic changes were assessed using label‐free mass spectrometry. Tissue‐specific Stat2 effects were studied in WT/ Stat2 −/− bone marrow chimera and using Cre‐lox recombination to delete Stat2 in pancreatic and duodenal homeobox 1 ( Pdx1 )‐expressing cells. Stat2 −/− mice were protected from caerulein‐ and l ‐arginine‐induced pancreatitis. Protection was independent of type I interferon signalling. Stat2 −/− mice had lower cytokine levels, including TNF‐α and IL‐10, and reduced NF‐κB nuclear localisation in pancreatic tissue compared with WT. Inhibition of TNF‐α improved (inhibition of IL‐10 worsened) caerulein‐induced pancreatitis in WT but not Stat2 −/− mice. Phosphoproteomics showed downregulation of MAPK mediators but accumulation of Ser412‐phosphorylated Tak1. Stat2 deletion in Pdx1 ‐expressing acinar cells ( Stat2 flox/Pdx1‐cre ) reduced pancreatic TNF‐α expression, but not histological injury or serum amylase. WT/ Stat2 −/− bone marrow chimera mice were protected from pancreatitis irrespective of host or recipient genotype. Stat2 loss results in disrupted signalling in pancreatitis, upstream of NF‐κB in non‐acinar and/or bone marrow‐derived cells. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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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) | 0.001 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".