Role of IKKβ-dependent NF-kB signaling in developmental and adult lymphatics

Abstract

however, this can be aggravated during the inflammatory disease and tumor metastasis. Additionally, lymphangiogenesis is critically regulated by vascular endothelial growth factor receptor-3 (VEGFR-3) and Prospero-related homeobox-1 (Prox1). Prox1 is an identified downstream target of the p50 dependent NF-kB signaling to regulate VEGFR-3 expression. However, the key molecule to regulate Prox1 expression in NF-kB signaling during lymphatic development is still unknown. Therefore, in this study, we explored the pivotal role of IKKβ, a catalytic subunit and key regulator of NF-kB signaling. Here we show that lymphatic vessel-specific deletion of IKKβ leads to subcutaneous edema, disrupted lymphatic plexus patterning, and restricted lymphatic sprouting at E15.5 in mouse embryos. Deletion of IKKβ postnatally induced defects in lymphatic valve maturation and maintenance. Notably, IKKβ downregulates Prox1 expression, and the LECs junctions are impaired during development. Moreover, mature lymphatic vessels are also dependent on IKKβ/NF-kB signaling. IKKβ depletion debilitated pathological lymphangiogenesis in the matured mouse cornea. Our findings demonstrate that IKKβ is a molecular switch, which regulates Prox1 expression and ultimately governs remodeling of lymphatic vessel (LV) patterning, lymphatic valve maintenance, and mature lymphatic functions.

Lymphangiogenesis, the development of lymphatic vessels, involves in the transportation of interstitial tissue fluid, supervision of natural defensive immune cells, and lipid absorption