Regulation of the neuroinflammatory response in autoimmune uveitis

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Research Abstract: Autoimmune uveitis is a serious sight-threatening condition defined by an autoreactive immune response against the retina and uveal tissues. In autoimmune uveitis, the retina and uveal tissues become a target of autoreactive immune cells, which leads to irreversible neural damages and can progress to significant visual impairment. Since the retina is a so-called “immune privileged” tissue protected by blood- retinal barrier, how immune cells gain entry into the retina and what antigen presenting cell (APC) populations are involved in local antigen presentation have been a long discussion. This proposal describes aims to elucidate an innovative mechanism whereby retinal microglia mediate autoreactive immune cell entry into the retina. Microglia are the resident immune cells of the central nervous system, including the retina, and function in the homeostatic maintenance of the neuro-retinal microenvironment. The role and function of microglia in disease progression is not well understood due to their multiple phenotypes and/or different stages of activation that are associated with either harmful or beneficial effects in disease pathogenesis. Our recent work demonstrated that microglial depletion inhibits development of EAU and that microglia are essential to disease induction. Interestingly, retinal microglia are significantly activated in response to EAU disease induction, quickly localizing to the retinal vasculature. However, our data indicated that microglia do not function as APCs in disease initiation, but in fact function to facilitate infiltration of a variety of circulating immune cells into the neuroretina. Our data highly suggested that microglia are key population that initiates blood-retinal barrier breakdown and that the circulating APCs and T cells that enter the retina trigger the subsequent vision altering auto-inflammatory response. However, the mechanisms by which this occurs remains unknown. In this proposal, we will elucidate the mechanism by which autoreactive immune cells gain entry into the retina and how the subsequent autoimmune response develops during disease progression in a mouse model of experimental autoimmune uveitis (EAU). We will begin by defining the initiating APC populations in EAU and the contribution of microglial expression of MHC-II during EAU disease progression. Moreover, we will identify the activation and kinetics of retinal microglia and infiltrating immune cells in EAU induction by using a single cell RNA sequence profiling. Lastly, we will define the role of SIRPalpha/CD47, an immune axis that is highly regulated in EAU and that functions in phagocytosis initiation and immune cell reactivity. Understanding the mechanism by which microglia initiate autoimmune uveitis will likely open new avenues of therapy for this disease as well as other blinding neovascular ophthalmic diseases.