nitrophenols and Diabetes-Mellitus--Type-1

Type 1 diabetes (T1D) is an organ-specific autoimmune disease characterized by hyperglycemia due to progressive loss of pancreatic beta cells. Immune-mediated beta cell destruction drives the disease, but whether beta cells actively participate in the pathogenesis remains unclear. Here, we show that during the natural history of T1D in humans and the non-obese diabetic (NOD) mouse model, a subset of beta cells acquires a senescence-associated secretory phenotype (SASP). Senescent beta cells upregulated pro-survival mediator Bcl-2, and treatment of NOD mice with Bcl-2 inhibitors selectively eliminated these cells without altering the abundance of the immune cell types involved in the disease. Significantly, elimination of senescent beta cells halted immune-mediated beta cell destruction and was sufficient to prevent diabetes. Our findings demonstrate that beta cell senescence is a significant component of the pathogenesis of T1D and indicate that clearance of senescent beta cells could be a new therapeutic approach for T1D.

Topics: Adolescent; Adult; Aged; Animals; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cellular Senescence; Child; Child, Preschool; Cohort Studies; Diabetes Mellitus, Type 1; Female; Fibroblasts; Humans; Hyperglycemia; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; THP-1 Cells; Young Adult

Impaired apoptosis in immune effector cells such as macrophages has been implicated in the development of autoimmune disease by promoting the breakdown of self-tolerance and the sustained production of cytotoxic molecules. Macrophages from nonobese diabetic (NOD) mouse, an animal model of human autoimmune diabetes, exhibit several defects that are causally linked to the onset and progression of the disease. In this context, we investigated whether NOD macrophages have a defect in a cell death pathway, and if that is the case, the mechanism underlying such dysregulation of cell death. We found that NOD macrophages were resistant to treatment with a broad spectrum of cell death stimuli, triggering both apoptotic and non-apoptotic death. Through analysis of intracellular signaling pathways along with the expression of apoptosis-related proteins, we found that atypical resistance to cell death was associated with an elevated expression of anti-apoptotic Bcl-X(L) but not the NF-κB signaling pathway in NOD macrophages. Further, ABT-737, which can inhibit Bcl-X(L) function, sensitized NOD macrophages to apoptosis induced by diverse apoptotic stimuli, thus restoring sensitivity to cell death. Taken together, our results suggest a macrophage-intrinsic defect in cell death as a potential mechanism that promotes an immune attack towards pancreatic β-cells and the development of autoimmune diabetes in NOD mice.

Topics: Animals; Apoptosis; bcl-X Protein; Biphenyl Compounds; Diabetes Mellitus, Type 1; Humans; Macrophages; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; NF-kappa B; Nitrophenols; Piperazines; Sulfonamides