TLR4 triggered complex inflammation in human pancreatic islets

Type 2 Diabetes (T2D) is strongly associated with obesity and inflammation. Toll-like receptor-4 (TLR-4) is the major pro-inflammatory pathway with its ligands and downstream products increased systemically in T2D and in at-risk individuals. Detailed mechanisms of the complex proinflammatory response in pancreatic islets remain unknown. In isolated human islets LPS induced IL-1 beta, IL-6, IL-8 and TNF production in a TLR4-dependent manner and severely impaired beta-cell survival and function. IL-6 antagonism improved beta-cell function. IL-8, which was identified specifically in a-cells, initiated monocyte migration, a process fully blocked by IL-8 neutralization. The TLR4 response was potentiated in obese donors; with higher IL-1 beta, IL-6 and IL-8 expression than in non-obese donors. TLR4 activation leads to a complex multi-cellular inflammatory response in human islets, which involves beta-cell failure, cytokine production and macrophage recruitment to islets. In obesity, the amplified TLR4 response may potentiate beta-cell damage and accelerate diabetes progression.