Fagundes, R.R.1,*, Peerlings, J.H.D.1, Zaldumbide, A.1
1CureOne Type-1 Diabetes Center, Leiden University Medical Center, Leiden, The Netherlands; *Presenting author (email: r.fagundes_rosa@lumc.nl)
Background: Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic insulin-producing β-cells are destroyed by autoreactive T cells. However, the events initiating β-cell damage before T-cell-mediated killing remain poorly understood. Current evidence suggests an interplay between genetic predisposition and environmental factors that promotes the production of type I interferons (e.g., IFNα and IFNβ), increasing β-cell immunogenicity by upregulating HLA expression and stimulating cytokine secretion, thereby enhancing β-cell visibility to the immune system. Recent findings from cancer research have highlighted a role for hypoxia, particularly through hypoxia-inducible factor 1α (HIF-1α), in regulating type I interferon responses, suggesting a potential early therapeutic intervention for T1D. We hypothesized that activation of the HIF-1α pathway protects β-cells against cellular stress, a crucial event preceding T1D onset.
Methods: EndoC-βH1 cells were stimulated with poly(I:C) to induce a type I interferon response and cultured under 5% O₂ or treated with the prolyl-hydroxylase domain (PHD) inhibitor DMOG. Lentiviral short hairpin RNA was used to selectively knock down PHD1 or PHD2.
Results: Incubation of EndoC-βH1 under 5% O₂ significantly reduced mRNA expression of the interferon-stimulated genes IFIH1, IFIT1, and ADAR1-p150 (n=3; P<0.05). DMOG activated HIF-1α signaling, evidenced by increased SLC2A1 and LDHA mRNA expression, while suppressing IFIH1 and IFIT1 mRNA expression (n=5; P<0.05). DMOG also reduced secretion of IP-10, IL-8, and TNFα (n=3; P<0.01). Knockdown of PHD1, but not PHD2, decreased poly(I:C)-induced IFIH1 and IFIT1 mRNA expression (n=3; P<0.05).
Discussion/Conclusion: These findings provide the first evidence that PHD inhibition, specifically targeting PHD1, attenuates type I interferon-driven inflammatory responses in human β-cells. PHD1 inhibition may therefore represent a promising early therapeutic strategy to limit inflammatory events preceding autoimmune β-cell destruction in T1D.