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 highly expressed in both β cells and macrophages. Global deletion of the gene encoding 12/15-LOX (Alox15) prevents diabetes in the NOD mouse (animal model for T1D) via reduction of proinflammatory cytokines produced by macrophages and islets. However, the role of 12/15-LOX in the macrophages during T1D development remains unclear. To address this issue, we generated myeloid lineage-specific Alox15 knockout mice (Alox15∆myel) on the NOD background and evaluated immune cell infiltration into the pancreas and in pancreatic lymph nodes, as well as diabetes outcome in these animals. Pancreas sections of Alox15∆Myel mice showed a decrease of lymphocyte infiltration compared to control littermates. Alox15∆Myel mice also showed a decreased frequency of IL-1β produced by macrophages (F480+IL1β+) and dendritic cells (CD11c+IL1β+) in the pLNs when compared to control mice. To clarify if Alox15 in myeloid cells mediates proinflammatory cytokines production by T cells, we performed a co-culture assay of Alox15-/- macrophages with naïve T cells. Alox15 deletion in macrophages impaired IFN-γ production from CD4+ T cells compared to WT macrophages. Furthermore, Alox15∆Myel mice showed a significant decrease in the incidence of spontaneous type 1 diabetes (<10%) compared to control mice (80%) (P<0.05). Alox15 deletion in macrophages led to increased β-cell mass and decreased insulitis in nondiabetic mice. Gene expression analysis in the islets showed increased expression of Pdx1 and Il-10 in islets of Alox15∆Myel mice. Together, these data suggest that myeloid-derived Alox15 promotes immune cell infiltration and inflammation in the pancreas leading to β-cell destruction and development of T1D.
A. Pineros: None. A. Kulkarni: None. K. Orr: None. L. Glenn: None. C.A. Reissaus: None. M. Hernandez-Perez: 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 Institutes of Health (R01DK105588, P30DK097512 to R.M.)