Proinflammatory Signaling in Islet Β Cells Propagates Invasion of Pathogenic Immune Cells in Autoimmune Diabetes
Type 1 diabetes is a disorder of immune tolerance that leads to death of insulin-producing islet β cells. We hypothesize that inflammatory signaling within β cells promotes progression of autoimmunity within the islet microenvironment. To test this hypothesis, we deleted the proinflammatory gene encoding 12/15-lipoxygenase (Alox15) in β cells of non-obese diabetic mice at a pre-diabetic time point when islet inflammation is a feature. Deletion of Alox15 leads to preservation of β cell mass, reduces populations of infiltrating T cells, and protects against spontaneous autoimmune diabetes in both sexes. Mice lacking Alox15 in β cells exhibit an increase in a population of β cells expressing the gene encoding the protein programmed death ligand 1 (PD-L1), which engages receptors on immune cells to suppress autoimmunity. Delivery of a monoclonal antibody against PD-L1 recovers the diabetes phenotype in knockout animals. Our results support the contention that inflammatory signaling in β cells promotes autoimmunity during type 1 diabetes progression.
Piñeros, A. R., Kulkarni, A., Gao, H., Orr, K. S., Glenn, L., Huang, F., Liu, Y., Gannon, M., Syed, F., Wu, W., Anderson, C. M., Evans-Molina, C., McDuffie, M., Nadler, J. L., Morris, M. A., Mirmira, R. G., & Tersey, S. A. (2022). Proinflammatory Signaling in Islet Β Cells Propagates Invasion of Pathogenic Immune Cells in Autoimmune Diabetes. https://doi.org/10.1016/j.celrep.2022.111011