PTGER4 inhibition in non-obese diabetic mice restores impaired IFNAR signaling, decreases chronic inflammatory signals and inhibits autoimmunity

Abstract

Abstract We recently demonstrated that dendritic cells (DCs) from autoimmune-prone non-obese diabetic (NOD) mice at prediabetic age (8–10 week) have a diminished IFN-alpha Receptor (IFNAR) response despite increased production of type 1 IFN. This impaired IFN response may result from chronic activation of inflammatory pathways that contribute to dysregulated innate activation. qPCR of innate targets showed that younger NOD mice (3 week old) did not yet display impaired IFNAR signaling, but already had higher IL-1. To understand the interplay between different innate signals, we compared gene expression of 5 key DC populations from prediabetic NOD mice and diabetes-resistant B6.g7 mice. Several inflammatory pathways including IL-1, Eicosanoids, and NFκB were higher in NOD DCs whereas type 1 IFN-response genes, especially those associated with tonic signal, were lower in prediabetic NOD mice. Analysis of potential upstream regulators of these changes identified increased PTGER4 signal and decreased IRF7. PTGER4 binds prostaglandin E2 (PGE2) and mediates specific aspects of both inflammatory and regulatory eicosanoid signaling. Interestingly, NOD mice treated with an inhibitor of PTGER4 displayed increased IFNAR signaling in DCs, but decreased IL-1, Nlrp3 and IFN-gamma production. These changes suggest restoration of cross-talk between key inflammatory mediators, namely that IFN-gamma and IL-1 can inhibit type 1 IFN and vice versa. Furthermore, mice treated with the PTGER4 antagonist display reduced autoimmune pathology, namely an increase in the number and percentage of healthy islets. These findings highlight PTGER4 as a potential target in type 1 diabetes, affecting several inflammatory pathways including IFNAR signaling.