The mtDNA nt7778 G/T Polymorphism Augments Formation of Lymphocytic Foci but Does Not Aggravate Cerulein-Induced Acute Pancreatitis in Mice

Abstract

A polymorphism in the ATP synthase 8 (ATP8) gene of the murine mitochondrial genome, G-to-T transversion at position 7778, has been suggested to increase susceptibility to multiple autoimmune diseases, including autoimmune pancreatitis (AIP). The polymorphism also induces mitochondrial reactive oxygen species generation, secretory dysfunction and β-cell mass adaptation. Here, we have used two conplastic mouse strains, C57BL/6N-mtAKR/J (B6-mtAKR; nt7778 G; control) and C57BL/6N-mtFVB/N (B6-mtFVB; nt7778 T), to address the question if the polymorphism also affects the course of cerulein-induced acute pancreatitis in mice. Therefore, two age groups of mice (3 and 12-month-old, respectively) were subjected to up to 7 injections of the secretagogue cerulein (50 µg/kg body weight) at hourly intervals. Disease severity was assessed at time points from 3 hours to 7 days based on pancreatic histopathology, serum levels of α-amylase and activities of myeloperoxidase (MPO) in lung tissue. A comparison of cerulein-induced pancreatic tissue damage and increases of α-amylase and MPO activities showed no differences between the age-matched groups of both strains. Interestingly, histological evaluation of pancreatic tissue of both untreated and cerulein-treated B6-mtAKR and B6-mtFVB mice also revealed the presence of infiltrates of immune cells surrounding ducts and vessels; a finding that is compatible with an early stage of AIP. After recovery from cerulein-induced pancreatitis (day 7 after the injections), 12-month-old B6-mtFVB mice but not B6-mtAKR mice displayed aggravated lymphocytic lesions. A comparison of 12-month-old mice with other age groups of both strains revealed that lymphocytic foci were largely absent in 3-month-old mice, while 24-month-old mice were more affected. Together, our data suggest that the mtDNA nt7778 G/T polymorphism does not aggravate cerulein-induced acute pancreatitis. Autoimmune-like lesions, however, may progress faster if additional tissue damage occurs.

Polymorphism in Murine mtATP8 Gene Correlates with Decreased Reactive Oxygen Species in Aging Hematopoietic Cells

“…At the same time a pancreatic β cell dysfunction, as well as an altered mitochondrial morphology in spleen cells, could be demonstrated (21). Pancreatic acini of 12-month-old mtFVB mice, by trend, had also enhanced ROS levels in comparison to mtAKR mice (20). However, in a corresponding in vivo study, no aggravation of acute pancreatitis in mtFVB strain was observed.…”

“…It would, thus, impact the whole respiratory chain, influencing ROS and ATP production. Recently, the impact of the nt7778 G/T polymorphism on cell function has been studied in different tissues (19)(20)(21)(22), as well as its effects on anxiety and stress reactivity (23,24).…”

In vitro studies implicate an imbalanced activation of dendritic cells in the pathogenesis of murine autoimmune pancreatitis

“…Most recently, we have identified in the same mouse strain CD4 + /CD44 high memory T-cells as an important link between genetic susceptibility and emergence of the disease [22]. Noteworthy, pancreatic autoimmune lesions have been shown in some mouse models to progress with increasing age [23], a phenomenon that might, at least in part, be related to a less efficient action of inhibitory immune cells in aged animals.…”