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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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Depletion of macrophages rescues the focally restricted inflammation phenotype in Ifnardel mice.(A) Representative H&E staining of the pancreas from WT and Ifnardel mice 48 hours after treatment. Mice were either treated with caerulein (regeneration model, left), caerulein plus clodronate filled liposomes (macrophage depletion, middle) or caerulein plus PBS filled liposomes (PBS control group, right) as described in the methods section (n = 3; original magnification, 100x). (B-D) Combined and individual scoring of pancreatic histological parameters from WT and Ifnardel mice 24 and 48 hours, and 5 days following caerulein-induced injury (plain bars) or caerulein-induced injury combined with macrophage depletion (striped bars) (n = 3–9 per group. Bars indicate mean +/- SD. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, Mann-Whitney-test).
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pone.0143735.g004: Depletion of macrophages rescues the focally restricted inflammation phenotype in Ifnardel mice.(A) Representative H&E staining of the pancreas from WT and Ifnardel mice 48 hours after treatment. Mice were either treated with caerulein (regeneration model, left), caerulein plus clodronate filled liposomes (macrophage depletion, middle) or caerulein plus PBS filled liposomes (PBS control group, right) as described in the methods section (n = 3; original magnification, 100x). (B-D) Combined and individual scoring of pancreatic histological parameters from WT and Ifnardel mice 24 and 48 hours, and 5 days following caerulein-induced injury (plain bars) or caerulein-induced injury combined with macrophage depletion (striped bars) (n = 3–9 per group. Bars indicate mean +/- SD. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, Mann-Whitney-test).

Mentions: Macrophages are recruited in the late regeneration phase after pancreatic injury (3–5 d) in WT mice (Fig 3B). To analyze the impact of the macrophage infiltration in Ifnardel mice in the early inflammation phase we depleted macrophages using clodronate liposomes [26]. Depletion was confirmed by staining for the macrophage marker F4/80 revealing a complete elimination of macrophages in the pancreas (S4 Fig). Depletion of the macrophages had no effect on the inflammatory response in WT mice (Fig 4). Interestingly, clodronate treated Ifnardel mice exhibited a distinct immune cell infiltration and underwent extensive tissue damage with a de-granulation of acinar cells compared to only caerulein treated Ifnardel mice. (Fig 4A, lower row, 48 h; Fig 4B). The formation of ADMs in Ifnardel mice was comparable to WT mice (Fig 4C). Moreover, in the absence of macrophages, Ifnardel mice revealed comparable pancreatitis as in WT mice (Fig 4D). Furthermore, the amount and the composition of immune cells revealed a similar distribution of CD45-positive immune cells, T- and B- lymphocytes as well as neutrophils (S5 Fig). Treatment with PBS filled liposomes, served as vesicle controls, revealed no differences to the regeneration model analyzing WT as well as Ifnardel mice, respectively (Fig 4A). Thus, infiltrating macrophages might protect the pancreas against the onset of a severe pancreatitis in Ifnardel mice.


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)

Depletion of macrophages rescues the focally restricted inflammation phenotype in Ifnardel mice.(A) Representative H&E staining of the pancreas from WT and Ifnardel mice 48 hours after treatment. Mice were either treated with caerulein (regeneration model, left), caerulein plus clodronate filled liposomes (macrophage depletion, middle) or caerulein plus PBS filled liposomes (PBS control group, right) as described in the methods section (n = 3; original magnification, 100x). (B-D) Combined and individual scoring of pancreatic histological parameters from WT and Ifnardel mice 24 and 48 hours, and 5 days following caerulein-induced injury (plain bars) or caerulein-induced injury combined with macrophage depletion (striped bars) (n = 3–9 per group. Bars indicate mean +/- SD. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, Mann-Whitney-test).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4664425&req=5

pone.0143735.g004: Depletion of macrophages rescues the focally restricted inflammation phenotype in Ifnardel mice.(A) Representative H&E staining of the pancreas from WT and Ifnardel mice 48 hours after treatment. Mice were either treated with caerulein (regeneration model, left), caerulein plus clodronate filled liposomes (macrophage depletion, middle) or caerulein plus PBS filled liposomes (PBS control group, right) as described in the methods section (n = 3; original magnification, 100x). (B-D) Combined and individual scoring of pancreatic histological parameters from WT and Ifnardel mice 24 and 48 hours, and 5 days following caerulein-induced injury (plain bars) or caerulein-induced injury combined with macrophage depletion (striped bars) (n = 3–9 per group. Bars indicate mean +/- SD. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, Mann-Whitney-test).
Mentions: Macrophages are recruited in the late regeneration phase after pancreatic injury (3–5 d) in WT mice (Fig 3B). To analyze the impact of the macrophage infiltration in Ifnardel mice in the early inflammation phase we depleted macrophages using clodronate liposomes [26]. Depletion was confirmed by staining for the macrophage marker F4/80 revealing a complete elimination of macrophages in the pancreas (S4 Fig). Depletion of the macrophages had no effect on the inflammatory response in WT mice (Fig 4). Interestingly, clodronate treated Ifnardel mice exhibited a distinct immune cell infiltration and underwent extensive tissue damage with a de-granulation of acinar cells compared to only caerulein treated Ifnardel mice. (Fig 4A, lower row, 48 h; Fig 4B). The formation of ADMs in Ifnardel mice was comparable to WT mice (Fig 4C). Moreover, in the absence of macrophages, Ifnardel mice revealed comparable pancreatitis as in WT mice (Fig 4D). Furthermore, the amount and the composition of immune cells revealed a similar distribution of CD45-positive immune cells, T- and B- lymphocytes as well as neutrophils (S5 Fig). Treatment with PBS filled liposomes, served as vesicle controls, revealed no differences to the regeneration model analyzing WT as well as Ifnardel mice, respectively (Fig 4A). Thus, infiltrating macrophages might protect the pancreas against the onset of a severe pancreatitis in Ifnardel mice.

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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Related in: MedlinePlus