Blood-retina barrier regulation and sterile inflammation in retinal homeostasis and disease

Abstract

Age-related macular degeneration (AMD) is the leading cause of central vision loss and blindness in the elderly. It is caused by a progressive loss of photoreceptors in the macula, thought to occur secondary to the damage in the retinal pigment epithelium (RPE). Although the disease burden is expected to rise in the coming years, the current therapeutic strategies remain limited. Recently, AMD has been associated with a state of chronic local low-grade inflammation in the retina. Dichotomous roles for the NLRP3 inflammasome, a large multiprotein oligomeric complex of the innate immune response, and its effector cytokine IL-18 have been implicated in the disease development and progression, as being protective in the neovascular (wet) AMD and pathological in the non-neovascular (dry) AMD, respectively. In the present study, the effects of systemic IL-18 administration were investigated in the JR5558 mouse strain, a novel genetic model of spontaneous retinal neovascularisation. It was demonstrated that IL-18 could prevent progression of developing neovascular lesions as well as enhance regression of fully established lesions in this animal model, providing further evidence for its therapeutic potential in the treatment of wet AMD. In addition, IL-18 was found to regulate the secretion of vascular endothelial growth factor (VEGF), the main driver of the pathological changes observed in neovascular AMD as well as in the JR5558 mouse model. Furthermore, IL-18 could promote the wound-healing process in the RPE and controlled the expression of tight junction proteins in endothelial cells to regulate the paracellular transport. The presence of the inflammasome components in and around the RPE of AMD patients was confirmed by immunohistochemical staining of specimens from human donors diagnosed with geographic atrophy, the end-stage form of dry AMD. Studying the molecular changes in the RPE in response to photoreceptor outer segment (POS) phagocytosis in vitro and in vivo, a novel link has been established between the daily POS phagocytosis and inflammasome activation in the RPE as part of the normal RPE physiology. Moreover, it was suggested that the POS phagocytosis might be an important regulator of VEGF synthesis in retinal homeostasis. The inner blood-retina barrier (iBRB) has evolved in order to protect the delicate tissue of the retina from potential blood-borne toxicity and maintain healthy local microenvironment and homeostasis. The regulation of the iBRB permeability in retinal homeostasis was addressed in a series of in vivo experiments, examining vascular leakage during the phagocytically active period of the RPE at 8 AM compared to 8 PM in several different mouse strains. It was demonstrated that the iBRB is physiologically a very dynamic structure, with its barrier properties cycling periodically during the day. A model of physiological iBRB regulation was proposed whereby the iBRB permeability is under the control of circadian rhythms and can be modulated by local factors, such as IL-18 and/or VEGF. These findings might have major clinical implications for drug delivery and development of new therapeutics for retinal diseases as well as provide a basis for novel approaches to modelling the disease pathology associated with geographic atrophy that would better reflect the phenotype observed in patients with dry AMD.