Background: Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world, affecting 1 in 7 Australians over the age of 50 and costing the Australian economy $16.6 billion annually (2009). AMD patients are seriously impacted by the loss of central vision, due to the death of the light-sensing photoreceptor cells and underlying retinal pigment epithelium. While environmental, lifestyle and genetic risk factors are well known to lead to the disease, at the molecular level inflammation has been identified as a central driver of disease progression and reducing inflammatory processes has been shown to ameliorate retinal degeneration. However, precisely how and where inflammation is first established and how this drives disease onset and progression remains unclear.
Methods: We used the photo-oxidative damage mouse model which mimics aspects of AMD including inflammation in the superior central retina. We subjected parasagittal cross sections of the eye to the Visium spatial gene expression technology to understand the spatial and temporal gene expression changes within the retina. Further, we used single cell sequencing data to increase resolution and gain insights into the complexity of gene expression with each spot.
Results: We identified highly localised changes of inflammatory genes and pathways within key retinal layers prior to the onset of retinal function impairment. We further provide evidence that with increasing damage gene expression changes radiate from the initial site of dysregulation, causing disruptions to retinal homeostasis in adjacent region. We also show that many of the most dysregulated genes are targeted by miRNAs that have been shown to play key roles in the inflammatory response in the retina.
Conclusion: Our study provides new insights into the role of inflammation in onset and progression of degeneration and offers novel cellular and gene targets to combat inflammation to prevent retinal damage.