Type 1 Diabetes Development Is Modulated by Select Lipid Signaling Derived from Beta Cells and Immune Cells

Type 1 diabetes (T1D) is a consequence of autoimmune destruction of β-cells and we find that the Ca 2+ -independent phospholipase A 2 β (iPLA 2 β) is induced in β-cells and immune cells and mitigation of iPLA 2 β attenuates β-cell death and T1D incidence. Activation of iPLA 2 β leads to generation of pro-inflammatory or anti-inflammatory bioactive lipids and we previously reported that iPLA 2 β activation favors M1 pro-inflammatory macrophage phenotype. Here, we utilized UPLC ESI-MS/MS protocols to assess the lipid profile generated by macrophages as a means to identify select lipids that are associated with T1D development. Macrophages were treated with DMSO (vehicle), IFNγ+LPS (to induce M1 polarization), or IL-4 (to induce M2 polarization) and at 16h, the media was collected and processed for assessment of eicosanoid class of bioactive lipids. Comparison of spontaneous diabetes-resistant C57BL/6J and spontaneous diabetes-prone NOD mice revealed that nearly all pro-inflammatory eicosanoids were elevated in NOD during the prediabetic phase, relative to C57. Theabundances increased in the NOD between 4-8 and decreased by 15 weeks, correlating with onset of insulitis. These findings are consistent with a higher inflammatory status in the NOD vs. C57. To assess contribution of iPLA 2 β to the lipid profile, macrophage responses in NOD were compared with those in NOD.iPLA 2 β -/+ . Such analyses revealed that production of select pro-inflammatory and anti-inflammatory lipids were decreased and increased, respectively, from macrophages and islets of NOD.iPLA 2 β -/+ , relative to age-matched NOD-WT, and this correlated with reduced T1D incidence in the NOD.iPLA 2 β -/+ . We further find that iPLA 2 β-derived lipids (iDLs) play a critical role in alternative splicing events that favor generation of pro-apoptotic variants of several factors (Bcl-x, capsase-9, and RAGE). These findings raise the possibility that iDLs are candidates for targeting to counter T1D development. Disclosure A. Nelson: None. M.A. Park: None. C. Chalfant: None. S. Ramanadham: None.