<b>Dual modulation of prostaglandin E</b><sub><strong>2</strong></sub><b> receptors, EP3 and EP4, protects beta-cell mass in a model of aggressive autoimmune inflammation</b>

<jats:p>&lt;p dir="ltr"&gt;Type 1 diabetes is driven by both beta-cell dysfunction and an autoreactive immune system, resulting in beta-cell destruction and hyperglycemia. We previously showed that pharmacological modulation of prostaglandin E&lt;sub&gt;2&lt;/sub&gt; (PGE&lt;sub&gt;2&lt;/sub&gt;) receptor (EP) signaling protects beta cells from cytokine-mediated death &lt;i&gt;ex vivo&lt;/i&gt; and relieves oxidative stress and maintains beta-cell identity in a mouse model of type 2 diabetes. Here we show that EP modulation protects against cytokine-mediated beta-cell death in islets from nonobese diabetic (NOD) mice. As PGE&lt;sub&gt;2 &lt;/sub&gt;can also alter immune cell phenotypes, we tested whether EP modulation prevents beta-cell destruction in a setting of aggressive autoimmunity &lt;i&gt;in vivo&lt;/i&gt;. Simultaneous blockade of the inhibitory EP3 receptor and activation of the stimulatory EP4 receptor delayed onset of hyperglycemia, prevented loss of beta-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 (Tregs). However, EP modulation altered islet cytokine expression, and within beta cells, preserved identity, sustained activation of the antioxidant factor, NRF2, and reduced evidence of senescence. Thus, the PGE&lt;sub&gt;2&lt;/sub&gt; signaling pathway is a potential target for protecting beta-cell mass under aggressive autoimmune attack to treat or prevent type 1 diabetes.&lt;/p&gt;</jats:p>