Type 1 diabetes (T1D) is a consequence of autoimmune destruction of pancreatic islet ?-cells and the underlying causes for this process are not completely understood. Yet to be defined are the roles of lipids generated in ?-cells and immune cells in this process. Islet ?-cells and immune cells express Ca2+- independent phospholipase A2? (iPLA2?), which hydrolyzes membrane phospholipids at the sn-2 position to generate lipids that can promote inflammatory responses. We hypothesize that iPLA2?-derived lipids (iDLs) provide critical signals linking immune cells, ?-cells, and ER stress with ?-cell death associated with autoimmune diabetes. In support, we find that (a) iPLA2? is induced by pro-inflammatory cytokines and cytokine-mediated ER stress and ?-cell apoptosis are reversed by iPLA2? inhibition, (b) ?-cells and immune cells in a spontaneous model of autoimmune diabetes (non-obese diabetic mice, NOD) express higher iPLA2? during the pre-diabetic phase, (c) administration of an iPLA2?-selective inhibitor (FKGK18) to NOD mice preserves ?-cells mass and reduces diabetes incidence, insulitis, and autoimmunity, (d) pre-treatment of immunodeficient mice with FKGK18 reduces adoptive transfer of diabetes by T-cells, (e) overexpression of iPLA2? in ?-cells accelerates and increases the incidence of diabetes in NOD, (f) reduction of iPLA2? in NOD mice mimics the protective effects seen with FKGK18 administration, (g) M1 inflammatory macrophage polarization is reduced with iPLA2? deficiency, and (h) there is feedback regulation between iPLA2? and ER stress, and between inflammation-related transcription factors and iPLA2?. Our hypothesis will be tested using whole animal (mouse models with altered iPLA2? expression on a NOD or immunodeficient-NOD background), mechanism-based in vitro, and translational (human T1D and autoantibody positive but not diabetic subjects) approaches through the following Aims: 1. Delineate the impact of iDLs generated by immune cells on autoimmune diabetes development. 2. Delineate the impact of iDLs generated by ?-cells on autoimmune diabetes development. 3. Delineate the cellular mechanisms by which iDLs induce ?-cell death in autoimmune diabetes. 4. Assess the contribution of iDLs to human T1D development.
These Aims will encompass generation of islet and immune cell lipidome during autoimmune diabetes development; adoptive transfer protocols to distinguish importance of iDLs generated by immune cells and ?-cells to diabetes development; co-culture assays to assess impact of iDLs on islet antigenicity; protein and message analyses to address link between ER stress, iDLs, and inflammation; ChIP and CRISPR/Cas9 analyses to examine transcriptional regulation of iPLA2?; and human subjects to asses the potential of iPLA2? as a biomarker of T1D susceptibility. Our long-term goal is to elucidate underlying mechanisms by which iPLA2?-derived lipid signals contribute to the pathogenesis of T1D, so that novel targets that might be candidates for drug intervention to counter T1D can be developed.
Diabetes mellitus is the most prevalent human metabolic disease, affecting 9.3% of Americans at a cost of approximately $245 billion/year. At present, there is no cure for diabetes and its continual rise in incidence makes diabetes mellitus a major public health crisis. The broad, long-term objective of our group is to develop novel strategies to preserve islet ?-cell mass so that normal ?-cell function can be maintained to prevent, delay the onset, and/or reduce progression of diabetes mellitus.
| Turk, John; White, Tayleur D; Nelson, Alexander J et al. (2018) iPLA2? and its role in male fertility, neurological disorders, metabolic disorders, and inflammation. Biochim Biophys Acta Mol Cell Biol Lipids : |
| Ashley, Jason W; Hancock, William D; Nelson, Alexander J et al. (2016) Polarization of Macrophages toward M2 Phenotype Is Favored by Reduction in iPLA2? (Group VIA Phospholipase A2). J Biol Chem 291:23268-23281 |
