Mouse RPE-Choroids mRNA profiles of 4-week subretinal injection of AAV-GFP/PDGF-D

Wet age-related macular degeneration (AMD) is a progressive degenerative disease and a leading cause of blindness in elderly population. AMD pathogenesis initiated by several signals generates cellular and molecular cross-talk, including complement pathway-mediated inflammation, macrophage activation, and upregulation of angiogenic and cytokine/chemokine pathways. However, the mechanism by which the complement system is activated in AMD is not well understood, although its components are found in the neovascular lesions of wet AMD patients. Here, we show that increased PDGF-D expression engaged both classical and alternative complement pathways and markedly increased chemokine and cytokine responses to activate macrophages, thereby triggering neuroinflammatory milieu and exacerbating pathological neovascularization. Pharmacological targeting of the complement C3a receptor using SB290157 alleviated neuroinflammation by blocking macrophage polarization and by inhibiting pathological choroidal neovascularization (CNV). Our study thus suggests that therapeutic strategies targeting both PDGF-D and complement-mediated inflammatory signals may open up new possibilities for the treatment of neovascular diseases.