Toll-like receptor 4 (TLR4) expression in human and murine pancreatic beta-cells affects cell viability and insulin homeostasis

CD11b positive macrophages were practically absent from isolated human islets obtained from non-diabetic brain-dead donors, and TLR4 mRNA and cell surface expression were restricted to β-cells. A significant loss of cell viability was observed in these β-cells indicating a possible relationship with TLR4 expression. Monitoring gene expression in β-cells exposed for 48h to the prototypical TLR4 ligand LPS showed a concentration-dependent increase in TLR4 and CD14 transcripts and decreased insulin content and secretion. TLR4-positive MIN6 cells were also LPS-responsive, increasing TLR4 and CD14 mRNA levels and decreasing cell viability and insulin content.Taken together, our data indicate a novel function for TLR4 as a molecule capable of altering homeostasis of pancreatic β-cells.Islets are small organ-like structures, which are rich in vasculature and are predominantly constituted of insulin-secreting β-cells and glucagon-producing α-cells. As the main target of autoimmunity that results in type 1 diabetes, β-cells have been the subject of numerous studies aiming to identify the mechanisms which cause the massive cell death that ultimately leads to overt disease. In the setting of autoimmunity, β-cells respond to the onslaught of proinflammatory cytokines produced by immune cells, such as interleukin (IL)-1β, tumor necrosis factor (TNF) -α and interferon- γ, which trigger the NF-κB pathway and promote transcription of genes that ultimately cause β-cell dysfunction and cell death [1].A promising treatment for type 1 diabetes is islet cell transplantation [2]. To this end, pancreata from brain-dead non-diabetic donors are selected and islets are harvested and purified in clean room facilities for infusion into the portal vein of diabetic patients. However, the isolation procedure employed to obtain purified islets is time-consuming and frequently fails to produce sufficient good quality islets to enable a successful engraftment. The low yield during the isolation proc