The pathogenesis of type 1 diabetes (T1D) involves the interaction of the immune system with β cells. 12/15-lipoxygenase (12/15-LOX), an enzyme involved in arachidonic acid metabolism, is expressed in both 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 production of proinflammatory mediators in islets and macrophages. However, the importance of 12/15-LOX in islets vs. macrophages remains unclear. To address this issue, we generated both inducible islet-cell-specific (NOD-Alox15∆islet) and myeloid-lineage-specific (Alox15∆myel) Alox15 knockout mice on the NOD background. Control female mice (Alox15loxp/loxp, Pdx1PB-CreERTM+, and LysM-Cre+) exhibited diabetes incidence greater than 75%, whereas both Alox15∆islet and Alox15∆myel showed a dramatic decrease in the incidence of diabetes (<10%, P<0.05). During the pre-diabetic phase (8 weeks of age), both control and Alox15∆islet mice 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), whereas Alox15∆myel mice had increased β-cell mass (1.56±0.02c g, P<0.05) and insulitis (score 1.18±0.08, P<0.05). We next examined the nature of immune cells present in the spleen and pancreatic lymph node (pLN). Alox15∆islet mice showed increased Tregs (CD4+FoxP3; P<0.05) with no changes in Th1 (CD4+IFNγ+) and Th17 (CD4+IL17+) cells in both the spleen and pLN compared to control mice (P=NS). Additionally, Alox15∆islet female mice exhibited decreased IL-1β production by dendritic cells. By contrast, Alox15∆myel mice showed only decreased pLN proinflammatory macrophages (F480+IL1β+) and dendritic cells (CD11c+IL1β+) compared to controls (P<0.05). Together, these data suggest that 12/15-LOX functions independently in both the islet and macrophage through different mechanisms, promoting the destruction of β cells during the pathogenesis of autoimmune T1D.


A. Pineros Alvarez: None. A. Kulkarni: None. K. Orr: None. L. Glenn: None. C.A. Reissaus: None. M. Hernandez-Perez: None. M. Gannon: None. M.J. McDuffie: Stock/Shareholder; Self; Adenosine Therapeutics, LLC. J. Nadler: None. R. Mirmira: None. M.A. Morris: Stock/Shareholder; Spouse/Partner; Sanofi US. S.A. Tersey: None.


National Institutes of Health (R01DK105588 to R.M., J.N.)

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