IL-27 regulates HIF-1α-mediated VEGFA response in macrophages of diabetic retinopathy patients and healthy individuals

Abstract

Human macrophages produce vascular endothelial growth factor A (VEGFA) for angiogenesis in diabetic retinopathy (DR). The regulatory function of IL-27 on human macrophages is not well understood. In particular, the effect of IL-27 on VEGFA response in human macrophages has not been investigated. We find that IL-27 suppresses VEGFA mRNA expression as well as protein secretion by human macrophages. The synergistic action of purinergic signaling and activation of hypoxia-inducible factor 1 alpha (HIF-1α) induces VEGFA production in a positive feedback loop. IL-27 signaling in human macrophages disrupts this positive feedback loop thus suppresses VEGFA production. Blockade of IL-27 signaling with a JAK2 antagonist reverses this downregulatory effect on HIF-1α and partially blocks the inhibitory effect on VEGFA production. Lastly, DR patient macrophages have a higher propensity to produce VEGFA and this is amplified by an in vitro challenge with the pro-inflammatory cytokine IL-1β. IL-27 suppresses VEGFA production by DR patient macrophages even in the presence of IL-1β challenge indicating a potential therapeutic use of IL-27 in the clinic.

Keywords: Diabetic retinopathy; HIF1α; Human macrophages; IL-27; The purinergic pathway; VEGFA.