| First Author | Heath H | Year | 2020 |
| Journal | J Pathol | Volume | 252 |
| Issue | 1 | Pages | 41-52 |
| PubMed ID | 32506441 | Mgi Jnum | J:301409 |
| Mgi Id | MGI:6504287 | Doi | 10.1002/path.5481 |
| Citation | Heath H, et al. (2020) Stat2 loss disrupts damage signalling and is protective in acute pancreatitis. J Pathol 252(1):41-52 |
| abstractText | 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-kappaB-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-alpha and IL-10, and reduced NF-kappaB nuclear localisation in pancreatic tissue compared with WT. Inhibition of TNF-alpha 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-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-kappaB in non-acinar and/or bone marrow-derived cells. (c) 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. |
