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

Miller KJ, Raulefs S, Kong B, Steiger K, Regel I, Gewies A, Kleeff J, Michalski CW - PLoS ONE (2015)

Bottom Line: Type I interferon constitutes an essential component of the combinational therapy against viral disease.Pancreas-specific ablation of interferon (alpha and beta) receptor 1 (Ifnar1) partially protected animals from caerulein-induced pancreatitis, as demonstrated by reduced tissue damage.Thus, type I interferon signaling in pancreatic acinar cells controls pancreatic homeostasis by affecting the macrophage-mediated inflammatory response in the pancreas.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Technische Universität München, Munich, Germany.

ABSTRACT
Type I interferon constitutes an essential component of the combinational therapy against viral disease. Acute pancreatitis is one side effect of type I interferon-based therapy, implying that activation of type I interferon signaling affects the homeostasis and integrity of pancreatic acinar cells. Here, we investigated the role of type I interferon signaling in pancreatic acinar cells using a caerulein-induced murine model of acute pancreatitis. Pancreas-specific ablation of interferon (alpha and beta) receptor 1 (Ifnar1) partially protected animals from caerulein-induced pancreatitis, as demonstrated by reduced tissue damage. Profiling of infiltrating immune cells revealed that this dampened tissue damage response correlated with the number of macrophages in the pancreas. Pharmacologic depletion of macrophages reversed the protective effect of Ifnar1 deficiency. Furthermore, expression of chemokine (C-C motif) ligand 2 (Ccl2), a potent factor for macrophage recruitment, was significantly increased in the Ifnar1-deficient pancreas. Thus, type I interferon signaling in pancreatic acinar cells controls pancreatic homeostasis by affecting the macrophage-mediated inflammatory response in the pancreas.

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Characterization of untreated Ifnardel mice reveals no differences to wild type mice.(A) qRT PCR analysis of mRNA levels of Ifnar1 from whole pancreatic tissue of untreated WT and Ifnardel mice. (n = 3 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib. **P<0.01, Mann-Whitney-test). (B) Representative H&E staining of the pancreas from 8 week old WT and Ifnardel mice without treatment (original magnification, 100x). (C) Pancreas weight/body weight ratio of 8 week old WT and Ifnardel mice without treatment (n = 7 per group. Bars indicate mean +/- SD). (D) Amylase, lipase and LDH (lactat-dehydrogenase) levels in the serum from of 8 week old WT and Ifnardel mice without treatment (n = 7 per group. Bars indicate mean +/- SD).
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pone.0143735.g001: Characterization of untreated Ifnardel mice reveals no differences to wild type mice.(A) qRT PCR analysis of mRNA levels of Ifnar1 from whole pancreatic tissue of untreated WT and Ifnardel mice. (n = 3 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib. **P<0.01, Mann-Whitney-test). (B) Representative H&E staining of the pancreas from 8 week old WT and Ifnardel mice without treatment (original magnification, 100x). (C) Pancreas weight/body weight ratio of 8 week old WT and Ifnardel mice without treatment (n = 7 per group. Bars indicate mean +/- SD). (D) Amylase, lipase and LDH (lactat-dehydrogenase) levels in the serum from of 8 week old WT and Ifnardel mice without treatment (n = 7 per group. Bars indicate mean +/- SD).

Mentions: Ifnardel mice have a knockout of the type I interferon receptor subunit 1 restricted to epithelial cells of the pancreas which leads to an interruption of the interferon alpha receptor expression (Fig 1A). The histological comparison of untreated eight weeks old C57-BL6/J (wild type/WT) mice with Ifnardel mice revealed no obvious differences between the two genotypes. H/E staining of WT and Ifnardel mice showed intact acinar lobes without any other histological abnormalities in the structure of the pancreas (Fig 1B). The body weight as well as the pancreas weight of WT mice corresponded to that of Ifnardel mice (S1 Fig). Further, the pancreas/body weight ratio was not significantly different between WT and Ifnardel mice (Fig 1C). Analysis of the blood serum levels of untreated WT and Ifnardel mice indicated comparable levels of amylase, lipase and LDH (Fig 1D).


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

Miller KJ, Raulefs S, Kong B, Steiger K, Regel I, Gewies A, Kleeff J, Michalski CW - PLoS ONE (2015)

Characterization of untreated Ifnardel mice reveals no differences to wild type mice.(A) qRT PCR analysis of mRNA levels of Ifnar1 from whole pancreatic tissue of untreated WT and Ifnardel mice. (n = 3 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib. **P<0.01, Mann-Whitney-test). (B) Representative H&E staining of the pancreas from 8 week old WT and Ifnardel mice without treatment (original magnification, 100x). (C) Pancreas weight/body weight ratio of 8 week old WT and Ifnardel mice without treatment (n = 7 per group. Bars indicate mean +/- SD). (D) Amylase, lipase and LDH (lactat-dehydrogenase) levels in the serum from of 8 week old WT and Ifnardel mice without treatment (n = 7 per group. Bars indicate mean +/- SD).
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Related In: Results  -  Collection

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pone.0143735.g001: Characterization of untreated Ifnardel mice reveals no differences to wild type mice.(A) qRT PCR analysis of mRNA levels of Ifnar1 from whole pancreatic tissue of untreated WT and Ifnardel mice. (n = 3 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib. **P<0.01, Mann-Whitney-test). (B) Representative H&E staining of the pancreas from 8 week old WT and Ifnardel mice without treatment (original magnification, 100x). (C) Pancreas weight/body weight ratio of 8 week old WT and Ifnardel mice without treatment (n = 7 per group. Bars indicate mean +/- SD). (D) Amylase, lipase and LDH (lactat-dehydrogenase) levels in the serum from of 8 week old WT and Ifnardel mice without treatment (n = 7 per group. Bars indicate mean +/- SD).
Mentions: Ifnardel mice have a knockout of the type I interferon receptor subunit 1 restricted to epithelial cells of the pancreas which leads to an interruption of the interferon alpha receptor expression (Fig 1A). The histological comparison of untreated eight weeks old C57-BL6/J (wild type/WT) mice with Ifnardel mice revealed no obvious differences between the two genotypes. H/E staining of WT and Ifnardel mice showed intact acinar lobes without any other histological abnormalities in the structure of the pancreas (Fig 1B). The body weight as well as the pancreas weight of WT mice corresponded to that of Ifnardel mice (S1 Fig). Further, the pancreas/body weight ratio was not significantly different between WT and Ifnardel mice (Fig 1C). Analysis of the blood serum levels of untreated WT and Ifnardel mice indicated comparable levels of amylase, lipase and LDH (Fig 1D).

Bottom Line: Type I interferon constitutes an essential component of the combinational therapy against viral disease.Pancreas-specific ablation of interferon (alpha and beta) receptor 1 (Ifnar1) partially protected animals from caerulein-induced pancreatitis, as demonstrated by reduced tissue damage.Thus, type I interferon signaling in pancreatic acinar cells controls pancreatic homeostasis by affecting the macrophage-mediated inflammatory response in the pancreas.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Technische Universität München, Munich, Germany.

ABSTRACT
Type I interferon constitutes an essential component of the combinational therapy against viral disease. Acute pancreatitis is one side effect of type I interferon-based therapy, implying that activation of type I interferon signaling affects the homeostasis and integrity of pancreatic acinar cells. Here, we investigated the role of type I interferon signaling in pancreatic acinar cells using a caerulein-induced murine model of acute pancreatitis. Pancreas-specific ablation of interferon (alpha and beta) receptor 1 (Ifnar1) partially protected animals from caerulein-induced pancreatitis, as demonstrated by reduced tissue damage. Profiling of infiltrating immune cells revealed that this dampened tissue damage response correlated with the number of macrophages in the pancreas. Pharmacologic depletion of macrophages reversed the protective effect of Ifnar1 deficiency. Furthermore, expression of chemokine (C-C motif) ligand 2 (Ccl2), a potent factor for macrophage recruitment, was significantly increased in the Ifnar1-deficient pancreas. Thus, type I interferon signaling in pancreatic acinar cells controls pancreatic homeostasis by affecting the macrophage-mediated inflammatory response in the pancreas.

Show MeSH
Related in: MedlinePlus