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.
Highlights
Type I interferons belong to the cytokine signaling molecules and protect the host by exhibiting an anti-viral and anti-tumor function [1,2,3]
The restriction of type I interferon signaling in these mice led to a focally limited pancreatitis after caerulein-induced injury with less tissue damage compared to WT mice
Ifnardel mice showed an increase of the chemokine Ccl2 in acute pancreatitis
Summary
Type I interferons belong to the cytokine signaling molecules and protect the host by exhibiting an anti-viral and anti-tumor function [1,2,3]. In the disease course of acute pancreatitis, pancreatic acinar cells have been shown to release chemokines [10, 11] and cytokines such as tumor necrosis factor, interleukins and interferons. Cytokines are known to activate monocytes and lead to a polarization of these cells into macrophages [16,17,18], whereas chemokines act as chemotactic guides to recruit macrophages to the inflamed pancreas [19]. In this regard, chemokine (C-C motif) ligand 2 (Ccl2) is one of the most important factors for the recruitment of macrophages [20]. Macrophages support the clearance of the destroyed tissue through phagocytosis of damaged and dead cells [21] and promote regeneration by supporting the resolution of inflammation, tissue renewal and angiogenesis [22, 23]
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