Choroidal neovascularization (CNV) is aberrant angiogenesis associated with exudative
age-related macular degeneration (AMD), a leading cause of
blindness in the elderly.
Inflammation has been suggested as a risk factor for AMD. The IKK2/NF-κB pathway plays a key role in the inflammatory response through regulation of the transcription of
cytokines,
chemokines,
growth factors and angiogenic factors. We investigated the functional role of IKK2 in development of the
laser-induced CNV using either Ikk2 conditional knockout mice or an IKK2 inhibitor. The
retinal neuronal tissue and RPE deletion of IKK2 was generated by breeding Ikk2(-/flox) mice with
Nestin-Cre mice. Deletion of Ikk2 in the retina caused no obvious defect in
retinal development or function, but resulted in a significant reduction in
laser-induced CNV. In addition, intravitreal or retrobulbar injection of an IKK2 specific chemical inhibitor,
TPCA-1, also showed similar inhibition of CNV. Furthermore, in vitro inhibition of IKK2 in ARPE-19 cells significantly reduced heat shock-induced expression of NFKBIA, IL1B, CCL2, VEGFA, PDGFA, HIF1A, and MMP-2, suggesting that IKK2 may regulate multiple molecular pathways involved in
laser-induced CNV. The in vivo
laser-induced expression of VEGFA, and HIF1A in RPE and choroidal tissue was also blocked by
TPCA-1 treatment. Thus, IKK2/NF-κB signaling appears responsible for production of pro-inflammatory and pro-angiogenic factors in
laser-induced CNV, suggesting that this intracellular pathway may serve as an important therapeutic target for aberrant angiogenesis in exudative AMD.