IL-8 receptor signaling as a novel target for angiogenic retinopathies

Diabetic retinopathy (DR) is characterized by chronic retinal inflammation and vascular remodeling that can threaten vision. Most current treatments are administered intravitreally and target vascular endothelial growth factor A (VEGF) but are often ineffective. Nevertheless, few alternative treatments, and no oral DR therapies, exist. Although IL-1β, TNFα, and IL-8 are upregulated along with VEGF within eyes with DR, they are not therapeutically targeted. IL-8 levels correlate with DR progression and resistance to anti-VEGF therapy, suggesting VEGF-independent contributions of IL-8-receptor signaling to DR. IL-1β and TNFα, in turn, enhance expression of pro-angiogenic CXCR2 ligands (e.g. IL-8, CXCL1) in human Müller cells (hMC). Despite investigation of CXCR2 roles in several angiogenic and fibrotic diseases, CXCR2 inhibitors have not been explored in DR models. In this study, we show protein upregulation of IL-8 and CXCL1, but no detectable VEGF in conditioned media (CM) from IL-1β and TNFα-stimulated hMC. Stimulation of human retinal microvascular endothelial cells (hRMEC) with this human Müller cell-conditioned media (hMC-CM), as well as directly with IL-8, upregulated hRMEC proliferation and migration. CXCR2 inhibition reduced pro-angiogenic hRMEC responses to hMC-CM and IL-8. Likewise, in vivo, in the oxygen-induced retinopathy (OIR) model, either genetic (Cxcr2^-/-) or pharmacologic (SB225002) CXCR2 inhibition reduced pre-retinal neovascularization without altering avascularity or VEGF expression. These findings suggest that: (a) Müller cells may link inflammatory and angiogenic responses in the retina, (b) CXCR2 activation may contribute to DR, and (c) CXCR2 inhibitors may be repurposed to reduce pre-retinal neovascularization, a key feature of proliferative DR.