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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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Pancreatic inflammation after caerulein- induced injury is limited in Ifnardel mice.(A) Representative H&E staining of the pancreas from WT and Ifnardel mice, 24 and 48 hours following caerulein-induced injury (original magnification, 100x). (B) Representative H&E staining of the pancreas from WT and Ifnardel mice, 3, 7 and 14 days following caerulein-induced injury (original magnification, 100x). (C-E) Combined and individual scoring of pancreatic histological parameters from WT and Ifnardel mice, 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<0.001, ****P<0.0001, Mann-Whitney-test).
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pone.0143735.g002: Pancreatic inflammation after caerulein- induced injury is limited in Ifnardel mice.(A) Representative H&E staining of the pancreas from WT and Ifnardel mice, 24 and 48 hours following caerulein-induced injury (original magnification, 100x). (B) Representative H&E staining of the pancreas from WT and Ifnardel mice, 3, 7 and 14 days following caerulein-induced injury (original magnification, 100x). (C-E) Combined and individual scoring of pancreatic histological parameters from WT and Ifnardel mice, 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<0.001, ****P<0.0001, Mann-Whitney-test).

Mentions: In WT mice, treatment with the cholecystokinin analog caerulein leads to pancreatitis [28, 29] concomitant with the activation of the type I interferon signaling (S2 Fig) To address the consequences of interferon signaling disruption during the inflammation and regeneration process we treated mice with caerulein to induce a pancreatitis in WT and Ifnardel mice [30]. The natural course of acute pancreatitis and the regenerative process consists of three distinctive and transient phases of inflammation, metaplasia and redifferentiation [31], last two summarized as regeneration. Within the inflammation phase (24–48 h after the last caerulein injection), WT mice underwent a broad tissue damage with a de-granulation of acini with immune cells infiltration. In contrast, Ifnardel mice exhibited less infiltrating immune cells and the pancreas was composed of normal, undamaged tissue and only scattered inflammatory areas were visible (Fig 2A). During the regeneration phase (3–14 d after the last caerulein injection) WT as well as Ifnardel mice completely regenerated. After 14 days, the exocrine compartment of WT and Ifnardel mice revealed a histological structure similar to the untreated counterparts (Fig 1B and Fig 2B). To quantify and evaluate the damage and changes of the pancreatic tissue during inflammation and regeneration, we developed a specific scoring system that characterizes different parameters of pancreatitis and pancreatitis related processes (S1 Table). The proportion of undamaged pancreas in WT mice was low during the inflammation phase and increased through the regeneration whereas in Ifnardel mice the level of intact tissue was consistently high (Fig 2C). Acinar-to-ductal-metaplasia (ADM) in WT mice was prominent directly after the induced injury but transient. Within 7 days, the number of ADMs decreased and the dedifferentiated cells seemed to convert back into acinar cells [32]. In contrast, the dedifferentiated state in Ifnardel mice stayed moderate during the inflammation and regeneration process (Fig 2D). No differences between the two genotypes could be observed in the analysis of edema and necrosis (S3 Fig). The assessment of the pancreatitis was based on the calculation of the grade with the distribution of the inflammation (pancreatitis = grade*distribution of inflammation). WT mice displayed strong pancreatitis which decreased during the regeneration of the organ. In contrast, Ifnardel mice developed a mild pancreatitis but a comparable level of the disease after 3 days of injury (Fig 2E). These data show that Ifnardel mice generated a focally restricted inflammation in regard to the distribution of the inflammation compared to WT mice. Nevertheless, the inflamed areas referred to the grade of inflammation were comparable between WT and Ifnardel mice (S3 Fig).


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)

Pancreatic inflammation after caerulein- induced injury is limited in Ifnardel mice.(A) Representative H&E staining of the pancreas from WT and Ifnardel mice, 24 and 48 hours following caerulein-induced injury (original magnification, 100x). (B) Representative H&E staining of the pancreas from WT and Ifnardel mice, 3, 7 and 14 days following caerulein-induced injury (original magnification, 100x). (C-E) Combined and individual scoring of pancreatic histological parameters from WT and Ifnardel mice, 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<0.001, ****P<0.0001, Mann-Whitney-test).
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getmorefigures.php?uid=PMC4664425&req=5

pone.0143735.g002: Pancreatic inflammation after caerulein- induced injury is limited in Ifnardel mice.(A) Representative H&E staining of the pancreas from WT and Ifnardel mice, 24 and 48 hours following caerulein-induced injury (original magnification, 100x). (B) Representative H&E staining of the pancreas from WT and Ifnardel mice, 3, 7 and 14 days following caerulein-induced injury (original magnification, 100x). (C-E) Combined and individual scoring of pancreatic histological parameters from WT and Ifnardel mice, 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<0.001, ****P<0.0001, Mann-Whitney-test).
Mentions: In WT mice, treatment with the cholecystokinin analog caerulein leads to pancreatitis [28, 29] concomitant with the activation of the type I interferon signaling (S2 Fig) To address the consequences of interferon signaling disruption during the inflammation and regeneration process we treated mice with caerulein to induce a pancreatitis in WT and Ifnardel mice [30]. The natural course of acute pancreatitis and the regenerative process consists of three distinctive and transient phases of inflammation, metaplasia and redifferentiation [31], last two summarized as regeneration. Within the inflammation phase (24–48 h after the last caerulein injection), WT mice underwent a broad tissue damage with a de-granulation of acini with immune cells infiltration. In contrast, Ifnardel mice exhibited less infiltrating immune cells and the pancreas was composed of normal, undamaged tissue and only scattered inflammatory areas were visible (Fig 2A). During the regeneration phase (3–14 d after the last caerulein injection) WT as well as Ifnardel mice completely regenerated. After 14 days, the exocrine compartment of WT and Ifnardel mice revealed a histological structure similar to the untreated counterparts (Fig 1B and Fig 2B). To quantify and evaluate the damage and changes of the pancreatic tissue during inflammation and regeneration, we developed a specific scoring system that characterizes different parameters of pancreatitis and pancreatitis related processes (S1 Table). The proportion of undamaged pancreas in WT mice was low during the inflammation phase and increased through the regeneration whereas in Ifnardel mice the level of intact tissue was consistently high (Fig 2C). Acinar-to-ductal-metaplasia (ADM) in WT mice was prominent directly after the induced injury but transient. Within 7 days, the number of ADMs decreased and the dedifferentiated cells seemed to convert back into acinar cells [32]. In contrast, the dedifferentiated state in Ifnardel mice stayed moderate during the inflammation and regeneration process (Fig 2D). No differences between the two genotypes could be observed in the analysis of edema and necrosis (S3 Fig). The assessment of the pancreatitis was based on the calculation of the grade with the distribution of the inflammation (pancreatitis = grade*distribution of inflammation). WT mice displayed strong pancreatitis which decreased during the regeneration of the organ. In contrast, Ifnardel mice developed a mild pancreatitis but a comparable level of the disease after 3 days of injury (Fig 2E). These data show that Ifnardel mice generated a focally restricted inflammation in regard to the distribution of the inflammation compared to WT mice. Nevertheless, the inflamed areas referred to the grade of inflammation were comparable between WT and Ifnardel mice (S3 Fig).

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