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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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Release of the chemoattractant Ccl2/MCP1 in untreated Ifnardel mice.(A) qRT PCR analysis of mRNA levels of the chemokines Cxcl9, Cxcl10, Cxcl11, Ccl2, Ccl4, Ccl5 and Ccl25 from whole pancreatic tissue of WT and Ifnardel mice harvested 4 hours following caerulein-induced injury (n = 3 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib). (B) qRT PCR analysis of mRNA levels of the chemokines Cxcl9, Cxcl10, Cxcl11, Ccl2, Ccl4, Ccl5 and Ccl25 from whole pancreatic tissue of untreated WT and Ifnardel mice (n = 7 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib. *P<0.05, unpaired Student´s t-test). (C) Immunohistochemical staining for MCP1-positive centro-acinar cells in the pancreas from WT and Ifnardel mice 24 hours following caerulein-induced injury or untreated and counting of the absolute number of positive cells on five separate high power fields for each section of untreated WT and Ifnardel mice and after 24 hours following caerulein-induced injury (n = 3–7 per group. Bars indicate mean +/- SD. ****P<0.0001, Mann-Whitney-test. Original magnification, 200x and 1000x).
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pone.0143735.g006: Release of the chemoattractant Ccl2/MCP1 in untreated Ifnardel mice.(A) qRT PCR analysis of mRNA levels of the chemokines Cxcl9, Cxcl10, Cxcl11, Ccl2, Ccl4, Ccl5 and Ccl25 from whole pancreatic tissue of WT and Ifnardel mice harvested 4 hours following caerulein-induced injury (n = 3 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib). (B) qRT PCR analysis of mRNA levels of the chemokines Cxcl9, Cxcl10, Cxcl11, Ccl2, Ccl4, Ccl5 and Ccl25 from whole pancreatic tissue of untreated WT and Ifnardel mice (n = 7 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib. *P<0.05, unpaired Student´s t-test). (C) Immunohistochemical staining for MCP1-positive centro-acinar cells in the pancreas from WT and Ifnardel mice 24 hours following caerulein-induced injury or untreated and counting of the absolute number of positive cells on five separate high power fields for each section of untreated WT and Ifnardel mice and after 24 hours following caerulein-induced injury (n = 3–7 per group. Bars indicate mean +/- SD. ****P<0.0001, Mann-Whitney-test. Original magnification, 200x and 1000x).

Mentions: Since untreated WT and Ifnardel mice showed no persistent macrophages in the pancreatic tissue (S6 Fig), we analyzed whether the early appearance of macrophages in Ifnardel mice 4 h after injury was based on early upregulation of chemokines. After caerulein treatment, both genotypes demonstrated moderate increased levels of Ccxl9, Cxcl10, Cxcl11, Ccl5, and CCcl25 and a distinct upregulation of Ccl2 and Ccl4 (Fig 6A). Without treatment, the chemokine expression in WT mice was low whereas the mRNA expression of Ccxl10 and Ccl4 was elevated in Ifnardel mice. Moreover, the level of Ccl2 was extremely high in these mice (Fig 6B). Ccl2, also known as MCP1, is a potent chemotactic factor for monocytes [34]. We performed IHC staining to detect MCP1 in WT and Ifnardel mice to validate our expression data on protein level. 24h after injury there was centroacinar staining in WT as well as in Ifnardel mice (Fig 6C). In untreated WT mice there were no MCP1-positive cells. In contrast, compared to untreated WT mice, Ifnardel mice exhibited an increased expression of MCP1 in the center of the acinar lobes (Fig 6C). The high expression of chemokines and the production of Ccl2/MCP1 in the centro-acinar cells of untreated Ifnardel mice support the hypothesis of an early recruitment of macrophages to the site of inflammation after 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)

Release of the chemoattractant Ccl2/MCP1 in untreated Ifnardel mice.(A) qRT PCR analysis of mRNA levels of the chemokines Cxcl9, Cxcl10, Cxcl11, Ccl2, Ccl4, Ccl5 and Ccl25 from whole pancreatic tissue of WT and Ifnardel mice harvested 4 hours following caerulein-induced injury (n = 3 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib). (B) qRT PCR analysis of mRNA levels of the chemokines Cxcl9, Cxcl10, Cxcl11, Ccl2, Ccl4, Ccl5 and Ccl25 from whole pancreatic tissue of untreated WT and Ifnardel mice (n = 7 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib. *P<0.05, unpaired Student´s t-test). (C) Immunohistochemical staining for MCP1-positive centro-acinar cells in the pancreas from WT and Ifnardel mice 24 hours following caerulein-induced injury or untreated and counting of the absolute number of positive cells on five separate high power fields for each section of untreated WT and Ifnardel mice and after 24 hours following caerulein-induced injury (n = 3–7 per group. Bars indicate mean +/- SD. ****P<0.0001, Mann-Whitney-test. Original magnification, 200x and 1000x).
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pone.0143735.g006: Release of the chemoattractant Ccl2/MCP1 in untreated Ifnardel mice.(A) qRT PCR analysis of mRNA levels of the chemokines Cxcl9, Cxcl10, Cxcl11, Ccl2, Ccl4, Ccl5 and Ccl25 from whole pancreatic tissue of WT and Ifnardel mice harvested 4 hours following caerulein-induced injury (n = 3 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib). (B) qRT PCR analysis of mRNA levels of the chemokines Cxcl9, Cxcl10, Cxcl11, Ccl2, Ccl4, Ccl5 and Ccl25 from whole pancreatic tissue of untreated WT and Ifnardel mice (n = 7 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib. *P<0.05, unpaired Student´s t-test). (C) Immunohistochemical staining for MCP1-positive centro-acinar cells in the pancreas from WT and Ifnardel mice 24 hours following caerulein-induced injury or untreated and counting of the absolute number of positive cells on five separate high power fields for each section of untreated WT and Ifnardel mice and after 24 hours following caerulein-induced injury (n = 3–7 per group. Bars indicate mean +/- SD. ****P<0.0001, Mann-Whitney-test. Original magnification, 200x and 1000x).
Mentions: Since untreated WT and Ifnardel mice showed no persistent macrophages in the pancreatic tissue (S6 Fig), we analyzed whether the early appearance of macrophages in Ifnardel mice 4 h after injury was based on early upregulation of chemokines. After caerulein treatment, both genotypes demonstrated moderate increased levels of Ccxl9, Cxcl10, Cxcl11, Ccl5, and CCcl25 and a distinct upregulation of Ccl2 and Ccl4 (Fig 6A). Without treatment, the chemokine expression in WT mice was low whereas the mRNA expression of Ccxl10 and Ccl4 was elevated in Ifnardel mice. Moreover, the level of Ccl2 was extremely high in these mice (Fig 6B). Ccl2, also known as MCP1, is a potent chemotactic factor for monocytes [34]. We performed IHC staining to detect MCP1 in WT and Ifnardel mice to validate our expression data on protein level. 24h after injury there was centroacinar staining in WT as well as in Ifnardel mice (Fig 6C). In untreated WT mice there were no MCP1-positive cells. In contrast, compared to untreated WT mice, Ifnardel mice exhibited an increased expression of MCP1 in the center of the acinar lobes (Fig 6C). The high expression of chemokines and the production of Ccl2/MCP1 in the centro-acinar cells of untreated Ifnardel mice support the hypothesis of an early recruitment of macrophages to the site of inflammation after 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