Stat2 loss disrupts damage signalling and is protective in acute pancreatitis.

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-kappa B-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 orl-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 postl-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- andl-arginine-induced pancreatitis. Protection was independent of type I interferon signalling.Stat2(-/-)mice had lower cytokine levels, including TNF-alpha and IL-10, and reduced NF-kappa B nuclear localisation in pancreatic tissue compared with WT. Inhibition of TNF-alpha improved (inhibition of IL-10 worsened) caerulein-induced pancreatitis in WT but notStat2(-/-)mice. Phosphoproteomics showed downregulation of MAPK mediators but accumulation of Ser412-phosphorylated Tak1. Stat2 deletion inPdx1-expressing acinar cells (Stat2(flox/Pdx1-cre)) reduced pancreatic TNF-alpha 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-kappa B in non-acinar and/or bone marrow-derived cells. (c) 2020 The Authors.The Journal of Pathologypublished by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.