Trained immunity in the retina and its influence on retinal degenerative disorders

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We and others have shown that when retinal microglia become pathologically activated by sustained stimulation, they release inflammatory mediators which are detrimental to vision-producing retinal neurons. However, it is not yet clear which molecular mechanisms underpin these exaggerated responses. Our preliminary data in the laser model of choroidal neovascularization indicates the presence of innate immune memory in the retina. Therefore, the goal of this study is to further investigate the role of trained immunity in the development of maladaptive inflammatory responses in the mouse retina with the aim of better understanding the immunological basis of retinal degenerative disorders. The proposed study is subdivided into two specific aims. In specific aim 1, we will endeavor to determine whether immunological memory can be imprinted in the retina by in vivo exposure to a metabolic or microbial microglial priming stimulus (peripheral or local application) to generate an enhanced inflammatory response to subsequent genetically or experimentally induced retinal damage. We will apply in vivo imaging, microglia histomorphometry and three different high throughput sequencing methods (RNA-seq, ATAC-Seq, ChIP-seq) in two different mouse models that mimic some important neuropathological features of human retinitis pigmentosa and atrophic age-related macular degeneration and determine how immune memory in the retina can modify disease pathogenesis. In specific aim 2, we will perform a proof-of concept study and determine whether blocking immunological memory in retinal microglia using cell-specific knockout of transforming growth factor-activated kinase 1 (Tak1), a key epigenetic pathway for immune training, can positively influence disease outcome in the two mouse models of retinal pathology. Successful completion of this work will uncover mechanisms governing immune cell activation in the retina and explore the potential interactions between long-term exposure to environmental and lifestyle stressors that may contribute to the development and progression of retinal pathologies. Importantly, completing the proposed work holds promise to identify critical mediators of trained immunity in the retina and pave the way towards new strategies for mitigating retinal pathologies with an inflammatory component.