Stat2 loss disrupts damage signalling and is protective in acute pancreatitis

ABSTRACT 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 severity of non-infective inflammation in the pancreas. Wild type (WT) and Stat2 −/− mice were injected intraperitoneally with cerulein or L-arginine. Specific cytokine-blocking antibodies were used in some experiments. Pancreata and blood were harvested 1h and 24h after the final dose of cerulein and up to 96h 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 cerulein- and L-arginine-induced pancreatitis. Protection was independent of type I interferon signalling. Stat2 −/− mice had lower cytokine levels including TNFα and IL-10 and reduced NF-kB nuclear localisation in pancreatic tissue compared to WT. Inhibition of TNFα improved (inhibition of IL-10 worsened) cerulein-induced pancreatitis in WT but not Stat2 −/− mice. Phosphoproteomics showed down-regulation of mitogen-activated protein kinase (MAPK) mediators but accumulation of Ser412-phosphorylated Tak1. Stat2 deletion in Pdx1 -expressing acinar cells ( Stat2 flox / Pdx1-cre ) reduced pancreatic TNFα expression, but not histological injury or serum amylase. WT/ Stat2 −/− bone-marrow chimera 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.