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 (<10%, P<0.05). During the prediabetic phase (8 weeks of age), both control and Alox15∆islet females exhibited similar β cell mass (0.70±0.08 g vs. 0.72±0.06 g, P=NS) and insulitis severity (score 1.89±0.17 vs. 1.74±0.19, P=NS). By contrast, at this same stage, Alox15∆islet mice showed increased Treg (CD4+FoxP3+) numbers in the spleen and pancreatic lymph node compared to controls (P<0.05) with no changes in Th1 (CD4+IFNγ+) and Th17 (CD4+IL17+) cells compared to control mice (P=NS). At 12 weeks of age, however, Alox15∆islet mice exhibited increased β-cell mass (0.40±0.05 g vs. 0.61±0.14 g, P=<0.05) and decreased insulitis severity (score 2.63±0.18 vs. 1.76±0.13, P=<0.05). Together, these data suggest that 12/15-LOX promotes islet inflammation and the destruction of β cells during the pathogenesis of autoimmune T1D, and supports the notion that inflammatory pathways intrinsic to the islet may initiate and propagate signals that exacerbate autoimmunity.
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 & Johnson, Medtronic, Sanofi. R. Mirmira: Advisory Panel; Self; Hibercell, Sigilon Therapeutics, Veralox Therapeutics. Employee; Spouse/Partner; Eli Lilly and Company. S.A. Tersey: None.
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK105588)