Loss of Ifnar1 in Pancreatic Acinar Cells Ameliorates the Disease Course of Acute Pancreatitis

Miller, Katharina; Raulefs, Susanne; Kong, Bo; Steiger, Katja; Regel, Ivonne; Gewies, Andreas; Kleeff, Jörg; Michalski, Christoph

doi:10.1371/journal.pone.0143735

Cited by 4 publications

(4 citation statements)

References 43 publications

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“…Previous studies into the role for type I IFN signalling in AP have used prolonged injection schedules and focussed on much later time points after the final injection (3–7 days). In these models, deletion of Ifnar1 partially improved tissue injury without an effect on cytokine mRNA levels [8,22]. Conversely, we find that pancreas‐specific deletion of Stat2 reduces TNF‐α levels but has no effect on tissue injury.…”

Section: Discussionmentioning

confidence: 76%

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Stat2 loss disrupts damage signalling and is protective in acute pancreatitis

Heath

Britton

Kudo

et al. 2020

The Journal of Pathology

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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 (Stat2flox/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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Section: Discussionmentioning

confidence: 76%

“…To date, studies of type I IFN in the pathogenesis of pancreatitis have focused on known canonical functions of the type I IFN receptor (Ifnar) and signalling [8], but not Stat2. In the current study, we tested the hypothesis that Stat2-mediated signalling plays a role in AP as a model of non-infective tissue inflammation.…”

Section: Introductionmentioning

confidence: 99%

Stat2 loss disrupts damage signalling and is protective in acute pancreatitis

Heath

Britton

Kudo

et al. 2020

The Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…Previous studies into the role for type I IFN signalling in acute pancreatitis have used prolonged injection schedules and focussed on much later time points after the final injection (3-7 days). In these models, deletion of Ifnar1 partially improved tissue injury without an effect on cytokine mRNA levels [8, 20]. Conversely, we find that pancreas-specific deletion of Stat2 reduces TNFα levels but has no effect on tissue injury.…”

Section: Discussionmentioning

confidence: 77%

Stat2 loss disrupts damage signalling and is protective in acute pancreatitis

Heath

Britton

Kudo

et al. 2019

Preprint

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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 (Stat2flox/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.

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“…IFNAR1 blocking antibody promotes arteriogenesis and regeneration in a murine hindlimb ischemia model [135]. Furthermore, loss of IFNAR1 in pancreatic acinar cells ameliorates the disease course of acute pancreatitis [136]. Similarly, Myd88/Ifnar1 double KO mice show normal liver regeneration after hepatectomy [137].…”

Section: Conflicting Studies?mentioning

confidence: 99%

Transflammation: Innate immune signaling in nuclear reprogramming

Meng

Chanda

Thandavarayan

et al. 2017

Advanced Drug Delivery Reviews

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Induction of pluripotency in somatic cells by retroviral overexpression of four transcription factors has revolutionized the field of stem cell biology and regenerative medicine. The efficient induction of pluripotency requires the activation of innate immune signaling in a process termed “transflammation” [1]. Specifically, the stimulation of pattern recognition receptors (PRRs) causes global alterations in the expression and activity of epigenetic modifiers to favor an open chromatin configuration. Activation of toll-like receptors (TLR) or RIG-1-like receptors (RLR) [2] trigger signaling cascades that result in NFκB or IRF-3 mediated changes in epigenetic plasticity that facilitate reprogramming. Another form of nuclear reprogramming is so-called direct reprogramming or transdifferentiation of one somatic cell to another lineage. We have shown that transdifferentiation of human fibroblasts to endothelial cells also involves transflammation [3]. Recently, we also identified reactive oxygen species (ROS) [4] and reactive nitrogen species (RNS) [5] as mediators of innate immune signaling in nuclear reprogramming. Innate immune signaling plays a key role in nuclear reprogramming by regulating DNA accessibility (Figure 1). Here, we review recent progress of innate immunity signaling in nuclear reprogramming and epigenetic plasticity.

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Loss of Ifnar1 in Pancreatic Acinar Cells Ameliorates the Disease Course of Acute Pancreatitis

Cited by 4 publications

References 43 publications

Stat2 loss disrupts damage signalling and is protective in acute pancreatitis

Stat2 loss disrupts damage signalling and is protective in acute pancreatitis

Stat2 loss disrupts damage signalling and is protective in acute pancreatitis

Transflammation: Innate immune signaling in nuclear reprogramming

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