IL-36g Augments Ocular Angiogenesis by Promoting the Vascular Endothelial Growth Factor-Vascular Endothelial Growth Factor Receptor Axis

Prevention of inflammatory angiogenesis is critical for suppressing chronic inflammation and inhibiting inflammatory tissue damage. Angiogenesis is particularly detrimental to the cornea because pathologic growth of new blood vessels can lead to marked vision impairment and even loss of vision. The expression of proinflammatory cytokines by injured tissues exacerbates the inflammatory cascade, including angiogenesis. IL-36 cytokine, a subfamily of the IL-1 superfamily, consists of three proin-flammatory agonists, IL-36a, IL-36b, and IL-36g, and an IL-36 receptor antagonist (IL-36Ra). Data from the current study indicate that human vascular endothelial cells constitutively expressed the cognate IL-36 receptor. The current investigation, for the first time, characterized the direct contri-bution of IL-36g to various angiogenic processes. IL-36g up-regulated the expression of vascular endothelial growth factors (VEGFs) and their receptors VEGFR2 and VEGFR3 by human vascular endo-thelial cells, suggesting that IL-36g mediates the VEGF-VEGFR signaling by endothelial cells. Moreover, by using a naturally occurring antagonist IL-36Ra in a murine model of inflammatory angiogenesis, this study demonstrated that blockade of endogenous IL-36g signaling results in significant retardation of inflammatory angiogenesis. The current investigation on the proangiogenic function of IL-36g provides novel evidence of the development of IL-36g -targeting strategies to hamper inflammatory angio-genesis. (Am J Pathol 2023, 193: 1740-1749; https://doi.org/10.1016/j.ajpath.2023.01.003)