Piñeros, Annie R.Kulkarni, AbhishekGao, HongyuOrr, Kara S.Glenn, LindseyHuang, FeiLiu, YunlongGannon, MaureenSyed, FarooqWu, WentingAnderson, Cara M.Evans-Molina, CarmellaMcDuffie, MarciaNadler, Jerry L.Morris, Margaret A.Mirmira, Raghavendra G.Tersey, Sarah A.2023-07-262023-07-262022Piñeros AR, Kulkarni A, Gao H, et al. Proinflammatory signaling in islet β cells propagates invasion of pathogenic immune cells in autoimmune diabetes. Cell Rep. 2022;39(13):111011. doi:10.1016/j.celrep.2022.111011https://hdl.handle.net/1805/34576Type 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.en-USPublisher PolicyMetabolismImmune checkpointImmunologyInsulinIsletPancreasSingle-cell RNA sequencingType 1 diabetesArticle