Dual Modulation of Prostaglandin E2 Receptors EP3 and EP4 Protects β-Cell Mass in a Model of Aggressive Autoimmune Inflammation

Type 1 diabetes is driven by both β-cell dysfunction and an autoreactive immune system, resulting in β-cell destruction and hyperglycemia. We previously showed that pharmacological modulation of prostaglandin E2 (PGE2) receptor (EP) signaling protects β-cells from cytokine-mediated death ex vivo and relieves oxidative stress and maintains β-cell identity in a mouse model of type 2 diabetes. Here we show that EP modulation protects against cytokine-mediated β-cell death in islets from nonobese diabetic (NOD) mice. Because PGE2 can also alter immune cell phenotypes, we tested whether EP modulation prevents β-cell destruction in a setting of aggressive autoimmunity in vivo. Simultaneous blockade of the inhibitory EP3 receptor and activation of the stimulatory EP4 receptor delayed onset of hyperglycemia, prevented loss of β-cell mass, and reduced insulitis in cyclophosphamide-treated female NOD mice. Despite reduced insulitis, there were no changes in several systemic T-cell populations, including regulatory T cells. However, EP modulation altered islet cytokine expression and, within β-cells, preserved identity, sustained activation of the antioxidant factor NRF2, and reduced evidence of senescence. Thus, the PGE2 signaling pathway is a potential target for protecting β-cell mass under aggressive autoimmune attack to treat or prevent type 1 diabetes. Article Highlights Modulation of prostaglandin E2 (PGE2) signaling improves β-cell health and survival. In this study, we examined whether these β-cell effects could be harnessed alongside known PGE2-mediated immunomodulation to ameliorate β-cell loss in a model of severe islet autoimmunity. Simultaneous pharmacological blockade of the EP3 receptor and activation of the EP4 receptor maintain mature β-cell mass, ameliorate the proinflammatory insulitic microenvironment, and alter β-cell stress responses in female nonobese diabetic mice undergoing aggressive inflammatory assault. EP modulation shows promise to support β-cell resiliency and reduce inflammation in a setting of autoimmune attack, such as type 1 diabetes.