Fighting inflammation to save cones: anti-inflammatory approaches to slow down cone degeneration in a mouse model of retinitis pigmentosa

The term Retinitis Pigmentosa (RP) defines a group of inherited dystrophies characterized by progressive degeneration of photoreceptors (PRs) and abnormalities in retinal pigment epithelium (RPE). In typical RP, primary degeneration of rods is followed by secondary death of cones. Affected individuals exhibit initial night blindness and constricted visual field, while central vision is eventually lost later, as cone cells degenerate. Unfortunately, there is no cure for RP. An important concept of RP pathophysiology is the biological link(s) between rod and cone death in this disease, where mutations are usually rod-specific and cones, genetically intact, degenerate as a consequence of a bystander effect. To note, the main cause of clinically significant vision loss is associated with cone, rather than with rod death. Although cones represent less than 5% of all PRs in the retina of most mammals, their role on human vision is crucial and their degeneration leads to a condition of irreversible vision loss. Survival of still-functioning cones following rod death enables patients with a night-blindness disease to lead normal lives for some time (Shelley et al., 2009). Previous studies of our laboratory and based on the rd10 mouse model of human RP demonstrated with molecular tools that inflammation emerges as a relevant component of RP, overcoming any other biological process expected to occur in this pathology. Here, we hypothesized that cones, non-primarily affected by the disease-causing mutation and long lasting with respect to rods, may suffer from side effects of such inflammatory process and finally die out. In this study, we employed a protocol of synthetic steroid administration to test the hypothesis that counteracting retinal inflammation concomitantly to the acute phase of PR degeneration may improve cone fate. Indeed, we demonstrated that systemic Dexamethasone treatment resulted in decreased inflammatory response at retinal level and this event was associated to improved cone survival and preservation of visual acuity in rd10 mice. Subsequently, we postulated that different classes of Mononuclear Phagocytes (MPs, such as microglia and monocytes-derived macrophages, primarily involved in the inflammatory response) played different roles in the chronic, noxious inflammatory response found at retinal level. The particular role of the CCL2 chemokine was assessed. Altogether, our findings suggest a link between local retinal inflammation and worsening of cone fate, opening the perspective of slowing down retinal decay and vision loss in RP by using anti-inflammatory strategies.