Nicotinamide Mononucleotide Attenuates Inflammatory Activation, Choroidal Neovascularization, and Lesion-Associated Remodeling

Purpose: To evaluate the therapeutic potential of nicotinamide mononucleotide (NMN) for modulating the neurovascular inflammatory microenvironment and blunting tissue remodeling in neovascular age-related macular degeneration (nAMD). Methods: A laser-induced choroidal neovascularization (CNV) model was established in C57BL/6J mice, and CNV lesion size was quantified on RPE/choroid flat mounts. Immunostaining evaluated myeloid cell accumulation and fibrosis-associated remodeling. Quantitative RT-PCR and Western blotting assessed inflammatory/angiogenic gene expression and signaling activation in the retina and RPE/choroid. In vitro, lipopolysaccharide (LPS)-stimulated bEnd.3 and primary mouse RPE cells and TGF-β-stimulated THP-1-derived macrophage cells were used to model inflammatory and profibrotic responses. Results: NMN treatment significantly reduced CNV size in the laser-induced CNV model. This was accompanied by decreased myeloid cell accumulation within CNV lesions. NMN attenuated inflammatory and angiogenesis-related gene expression in the RPE/choroid and neural retina and reduced downstream signaling activation. In vitro, NMN suppressed LPS-induced inflammatory and proangiogenic responses in primary RPE cells and bEnd.3 endothelial cells and inhibited NF-κB activation. NMN further attenuated tissue remodeling, as shown by reduced collagen I-positive area under prolonged and delayed dosing regimens, together with decreased F4/80-positive area and α-smooth muscle actin-positive area within CNV lesions. In TGF-β-induced THP-1-derived macrophage cells, NMN suppressed profibrotic responses. Conclusions: Our findings indicate that NMN reduces inflammatory signaling and alleviates the inflammatory microenvironment in CNV, accompanied by decreased angiogenesis-related gene expression and fibrosis-related remodeling. By attenuating inflammatory activation and tissue remodeling processes, NMN warrants further evaluation as an adjunctive approach to limit CNV progression and late-stage tissue remodeling in nAMD.