Retinal degeneration (RD) is a characteristic of inherited retinopathy and age-related macular degeneration and can lead to severe visual impairment and eventual blindness. There are a wide range of factors that can initiate retinal degeneration, but ultimately the endpoint is photoreceptor cell death. Identifying unifying pro-death or pro-survival mechanisms in these diseases has potential to offer global therapeutic approaches for facilitating protection of visual function across multiple diseases.
Stressed and dying cells can trigger immune reactions leading to pathological consequences that are often perpetuating in nature. In the retina we see this in the migration of microglia towards the photoreceptor outer nuclear layer and subretinal space, areas devoid of immune cells in healthy tissue. In a variety of animal models of RD it appears that inhibiting or slowing migration of immune cells to the photoreceptors coincides with preservation of photoreceptor cell numbers and prolonged visual function. To date, immune-related research in the retina has focused mainly on microglia and infiltrating mononuclear cells. The innate immune capacity of retinal neurons, distinct from that of immune cells, remains to be explored in RD representing a substantial knowledge gap.
In this proposal we will characterize innate immune Pattern Recognition Receptor (PRR)-signalling in human induced pluripotent stem cell hiPSC–derived photoreceptor precursor cells (PPCs), and iPSC–derived retinal organoids (ROs). Our preliminary data leads us to hypothesize that PRRs are engaged in photoreceptors in response to cellular stress, resulting in activation of gene signatures that attract and activate microglia/myeloid cells. It is possible that photoreceptor immune signalling could be an early modifiable factor in the initiating stages of retinal disease attracting microglia/myeloid cells toward the outer retina driving a cycle of pathogenic inflammatory signalling. Data generated has potential to provide new gene-agnostic therapeutic targets to slow the progression of blindness across multiple retinal degenerative diseases.
