Type 1 diabetes (T1D) has become viewed as an autoimmune disease initiated and propagated by stress responses in islet β cells. The integrated stress response (ISR) is activated upon inflammatory signaling and delimits protein production through the actions of phospho-eIF2α. We hypothesized that inhibition of the β cell ISR will protect against β cell immunogenicity and development of T1D. To test this hypothesis, we studied the effect of ISR inhibition using ISRIB (p-eIF2α inhibitor) and VLX-10 (human 12-lipoxygenase inhibitor) on the response of isolated human islets and EndoC-βH1 cells to inflammatory cytokines (IFN-γ+IL-1β) and studied the effect of ISR inhibition on T1D outcomes in NOD mice. Human islets exposed to cytokines exhibited an increase in p-eIF2α and suppression of mRNA translation initiation (by polysome profiling) , consistent with activation of the ISR. Inhibition of the ISR with ISRIB or VLX-10promoted production of PD-L1, an immune checkpoint protein that suppresses the immune response, in human islets and EndoC-βH1 cells. This finding suggested that blockade of the ISR in β cells might thwart immune attack. To assess if inhibition of the ISR using the human-specific 12-lipoxygenase inhibitor VLX-10modifies T1D progression, we generated mice in which the gene encoding mouse 12-lipoxygenase gene was replaced by the corresponding human gene. These “humanized” mice were subsequently backcrossed onto the NOD background, then treated in the prediabetic phase with VLX-1005. Male and female humanized mice developed T1D at the expected frequency, but those receiving VLX-10showed significant delay of T1D onset. Consistent with the suppression of autoimmunity, insulitis was significantly reduced and β cell mass was significantly increased in treated animals. Our results support the targeting of the ISR through inhibition of the 12-lipoxygenase enzyme provides an opportunity for the modification of T1D disease progression.
F.Huang: None. A.Kulkarni: None. F.Syed: None. D.J.Maloney: Employee; Veralox Therapeutics. S.A.Tersey: n/a. R.G.Mirmira: None.