Limits...
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.

Show MeSH

Related in: MedlinePlus

Macrophages are the predominant immune cells infiltrating the pancreas following caerulein-induced injury in Ifnardel mice.(A) The absolute number of CD45-positive immune cells, B220-positive B-lymphocytes, CD3-positive T-lymphocytes and MPO-positive neutrophils was counted in five separate high power fields for each section of untreated WT and Ifnardel mice and 24, 48 hours, 3, 5, 7 and 14 days following caerulein-induced injury (n = 3–9 per group. Bars indicate mean +/- SD. *P<0.05, **P<0.01, ****P<0.0001, Student´s t-test). (B) Immunohistochemical staining for F4/80-positive macrophages in the pancreas from WT and Ifnardel mice 24h following caerulein-induced injury and counting of the absolute number of positive cells in five separate high power fields for each section of untreated WT and Ifnardel mice and 24, 48 hours, 3, 5, 7 and 14 days following caerulein-induced injury (n = 3–9 per group. Bars indicate mean +/- SD. *P<0.05, ****P<0.0001, Student´s t-test. Original magnification, 200x and 650x).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4664425&req=5

pone.0143735.g003: Macrophages are the predominant immune cells infiltrating the pancreas following caerulein-induced injury in Ifnardel mice.(A) The absolute number of CD45-positive immune cells, B220-positive B-lymphocytes, CD3-positive T-lymphocytes and MPO-positive neutrophils was counted in five separate high power fields for each section of untreated WT and Ifnardel mice and 24, 48 hours, 3, 5, 7 and 14 days following caerulein-induced injury (n = 3–9 per group. Bars indicate mean +/- SD. *P<0.05, **P<0.01, ****P<0.0001, Student´s t-test). (B) Immunohistochemical staining for F4/80-positive macrophages in the pancreas from WT and Ifnardel mice 24h following caerulein-induced injury and counting of the absolute number of positive cells in five separate high power fields for each section of untreated WT and Ifnardel mice and 24, 48 hours, 3, 5, 7 and 14 days following caerulein-induced injury (n = 3–9 per group. Bars indicate mean +/- SD. *P<0.05, ****P<0.0001, Student´s t-test. Original magnification, 200x and 650x).

Mentions: Next, we analyzed the number and composition of infiltrating cells in untreated WT and Ifnardel mice and during the inflammation and regeneration phase. Staining of the common immune cell marker CD45 showed augmented recruitment of immune cells in WT mice in comparison to Ifnardel mice (Fig 3A). Specific staining for B220-positive B-lymphocytes, CD3-positive T-lymphocytes and myeloperoxidase-positive neutrophils revealed no significant differences in the distribution of these immune cells between WT and Ifnardel mice (Fig 3A). Interestingly, there were striking differences in the quantity of F4/80-positive macrophages during the inflammation and regeneration process between WT and Ifnardel mice. WT mice displayed scarce infiltration of macrophages during the inflammation phase (24–48 h) and early regeneration phase (3 d) with an increase in the number of cells in the later regeneration phase (5–7 d) (Fig 3B). In contrast, macrophages were the predominant immune cell type in the pancreas of Ifnardel mice. During the inflammation phase (24–48 h) and the first phase of the regeneration (3 d) there were significantly more F4/80-positive cells in Ifnardel compared to WT mice. During the later regeneration phase, the number of macrophages decreased in Ifnardel mice (Fig 3B). 14 days after tissue injury, there were equally low numbers of macrophages in both genotypes. These data indicate that limitation of type 1 interferon signaling in acinar cells of the pancreas results in aberrant immune cell recruitment after caerulein- induced injury.


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)

Macrophages are the predominant immune cells infiltrating the pancreas following caerulein-induced injury in Ifnardel mice.(A) The absolute number of CD45-positive immune cells, B220-positive B-lymphocytes, CD3-positive T-lymphocytes and MPO-positive neutrophils was counted in five separate high power fields for each section of untreated WT and Ifnardel mice and 24, 48 hours, 3, 5, 7 and 14 days following caerulein-induced injury (n = 3–9 per group. Bars indicate mean +/- SD. *P<0.05, **P<0.01, ****P<0.0001, Student´s t-test). (B) Immunohistochemical staining for F4/80-positive macrophages in the pancreas from WT and Ifnardel mice 24h following caerulein-induced injury and counting of the absolute number of positive cells in five separate high power fields for each section of untreated WT and Ifnardel mice and 24, 48 hours, 3, 5, 7 and 14 days following caerulein-induced injury (n = 3–9 per group. Bars indicate mean +/- SD. *P<0.05, ****P<0.0001, Student´s t-test. Original magnification, 200x and 650x).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0143735.g003: Macrophages are the predominant immune cells infiltrating the pancreas following caerulein-induced injury in Ifnardel mice.(A) The absolute number of CD45-positive immune cells, B220-positive B-lymphocytes, CD3-positive T-lymphocytes and MPO-positive neutrophils was counted in five separate high power fields for each section of untreated WT and Ifnardel mice and 24, 48 hours, 3, 5, 7 and 14 days following caerulein-induced injury (n = 3–9 per group. Bars indicate mean +/- SD. *P<0.05, **P<0.01, ****P<0.0001, Student´s t-test). (B) Immunohistochemical staining for F4/80-positive macrophages in the pancreas from WT and Ifnardel mice 24h following caerulein-induced injury and counting of the absolute number of positive cells in five separate high power fields for each section of untreated WT and Ifnardel mice and 24, 48 hours, 3, 5, 7 and 14 days following caerulein-induced injury (n = 3–9 per group. Bars indicate mean +/- SD. *P<0.05, ****P<0.0001, Student´s t-test. Original magnification, 200x and 650x).
Mentions: Next, we analyzed the number and composition of infiltrating cells in untreated WT and Ifnardel mice and during the inflammation and regeneration phase. Staining of the common immune cell marker CD45 showed augmented recruitment of immune cells in WT mice in comparison to Ifnardel mice (Fig 3A). Specific staining for B220-positive B-lymphocytes, CD3-positive T-lymphocytes and myeloperoxidase-positive neutrophils revealed no significant differences in the distribution of these immune cells between WT and Ifnardel mice (Fig 3A). Interestingly, there were striking differences in the quantity of F4/80-positive macrophages during the inflammation and regeneration process between WT and Ifnardel mice. WT mice displayed scarce infiltration of macrophages during the inflammation phase (24–48 h) and early regeneration phase (3 d) with an increase in the number of cells in the later regeneration phase (5–7 d) (Fig 3B). In contrast, macrophages were the predominant immune cell type in the pancreas of Ifnardel mice. During the inflammation phase (24–48 h) and the first phase of the regeneration (3 d) there were significantly more F4/80-positive cells in Ifnardel compared to WT mice. During the later regeneration phase, the number of macrophages decreased in Ifnardel mice (Fig 3B). 14 days after tissue injury, there were equally low numbers of macrophages in both genotypes. These data indicate that limitation of type 1 interferon signaling in acinar cells of the pancreas results in aberrant immune cell recruitment after caerulein- induced injury.

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