Islet-Autonomous Inflammatory Signaling Propagates Autoimmunity and Promotes Diabetes in Nonobese Diabetic Mice

The type 1 diabetes (T1D) pathogenesis has been viewed as being initiated and propagated by directed autoimmunity against islet β cells. In recent years, we and others have taken a new perspective placing the β cell itself as the initiating cell. 12/15-lipoxygenase (12/15-LOX), an enzyme involved in arachidonic acid metabolism, is expressed in β cells and macrophages. Global deletion of the gene encoding 12/15-LOX (Alox15) prevents diabetes in the NOD mouse model of T1D via reduction in cellular production of proinflammatory mediators in islets and macrophages. We hypothesized that this protective phenotype largely emanates from the loss of 12/15-LOX in the islet rather than immune cells. To test this hypothesis, we generated inducible islet-specific Alox15 knockout mice (Alox15∆islet) on the NOD background. Control female mice (Alox15loxp/loxp;Pdx1PB-CreERTM/+) exhibited diabetes incidence greater than 75%, whereas Alox15∆islet females showed a significant decrease in the incidence of diabetes ( Disclosure A. Pineros: None. A. Kulkarni: None. M. Hernandez-Perez: None. K. Orr: None. L. Glenn: None. C.A. Reissaus: None. M. Gannon: None. M.J. McDuffie: None. J. Nadler: None. M.A. Morris: Stock/Shareholder; Spouse/Partner; Becton, Dickinson and Company, Bristol-Myers Squibb, Johnson \u0026 Johnson, Medtronic, Sanofi. R. Mirmira: Advisory Panel; Self; Hibercell, Sigilon Therapeutics, Veralox Therapeutics. Employee; Spouse/Partner; Eli Lilly and Company. S.A. Tersey: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK105588)