Caffeine suppresses inflammation and subretinal fibrosis through modulation of the thrombospondin-1-Bim axis

Age-related macular degeneration (AMD) in the aging population frequently leads to vision impairment. Treatment for neovascular AMD (nAMD) focuses on the tortuous leaky vessels that typify choroidal neovascularization (CNV). Subretinal fibrosis in nAMD patients is more challenging to treat, as few effective options exist. This fibrosis notably impairs vision and typically develops in patients who do not fully respond to current treatments. To gain a better understanding of pathways that could be utilized to subvert subretinal fibrosis, we examined the role Bim, a pro-apoptotic mediator in the intrinsic cell death pathway, and thrombospondin-1 (TSP1), a key regulator of ocular angioinflammatory processes, have in moderating fibrosis. Here we show caffeine treatment significantly reduced subretinal fibrosis in the mouse laser photocoagulation model consistent with its known ability to enhance mononuclear phagocyte (MP) clearance and reduce CNV. Since the TSP1-Bim axis facilitates MP clearance, suppresses inflammation, prevents subretinal fibrosis and CNV, we assessed its necessity for the mitigation of fibrosis by caffeine. We show that caffeine did not prevent subretinal fibrosis or CNV in mice lacking Bim or TSP1. Thus, caffeine utilizes the intrinsic death pathway though TSP1-Bim axis to subvert subretinal fibrosis, likely by suppressing inflammation during CNV.