Interleukin-18 has antipermeablity and antiangiogenic activities in the eye: reciprocal suppression with VEGF

Interleukin-18 (IL-18) is increased along with IL-1β by activation of the inflammasome and has been implicated in inflammatory and autoimmune diseases, but its role in the eye is uncertain. In patients with macular edema due to retinal vein occlusion, intraocular IL-18 levels increased significantly (P < 0.001) after treatment with ranibizumab particularly in patients with high baseline IL-18 which correlated with good visual outcome (P < 0.05). In mice with ischemic retinopathy, suppression of VEGF caused an increase in IL18 mRNA due to an increase in IL-18-positive myeloid cells. VEGF significantly and specifically inhibited IL-18 production by myeloid cells stimulated with lipopolysaccharide (P < 0.001). Intraocular injection of IL-18 reduced VEGF-induced leakage and neovascularization, and reversed VEGF-induced suppression of Claudin5 expression and Claudin 5 labeling of vascular tight junctions. Injection of IL-18 also increased expression of Thrombospondin 1 and reduced ischemia-induced retinal neovascularization relevant to diabetic retinopathy and subretinal neovascularization relevant to neovascular age-related macular degeneration. Thus, VEGF and IL-18 suppress each other's production and effects on the vasculature suggesting that IL-18 may provide benefit in multiple retinal/choroidal vascular diseases.