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Stat2 loss disrupts damage signalling and is protective in acute pancreatitis
Author(s) -
Heath Helen,
Britton Gary,
Kudo Hiromi,
Renney George,
Ward Malcolm,
Hutchins Robert,
Foster Graham R,
Goldin Robert,
Alazawi William
Publication year - 2020
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5481
Subject(s) - stat2 , cytokine , inflammation , pancreatitis , pdx1 , tumor necrosis factor alpha , cancer research , acute pancreatitis , biology , chemistry , medicine , endocrinology , immunology , phosphorylation , microbiology and biotechnology , stat3 , stat , islet , insulin
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.