Functional significance of NETosis to intraocular inflammation

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Abstract Uveitis can result in severe visual impairment, and ranks fifth among causes of blindness in the United States. Yet we are still trying to develop a complete understanding of the mechanisms of non- infectious intraocular inflammation. Expanding our knowledge of the role innate immunity plays in non- infectious inflammatory disease will provide important insights to complement the large body of literature on the role adaptive immunity, particularly T-cells, play in intraocular inflammation. Neutrophils are important innate immunity effector cells, and have been identified in human eyes with uveitis as well as in experimental models of uveitis. Neutrophils can undergo a form of cell death known as NETosis as part of the host response to infection, or during sterile inflammation in autoimmune diseases. The resulting neutrophil extracellular traps (NETs) can be pro-inflammatory, and blocking NETosis has been shown to ameliorate inflammation in animal models of systemic inflammatory diseases. Despite the presence of neutrophils in inflamed eyes, the presence of NETs in uveitis has not been explored. We have preliminary data identifying NETs in an animal model of anterior and intermediate uveitis, primed mycobacterial uveitis (PMU). We propose using both PMU and experimental autoimmune uveitis (EAU) to determine if NETs are generally present in the case of intraocular inflammation (Aim 1). We will also determine the functional importance of NETs to uveitis by testing the sufficiency of NETs to generate uveitis and the impact of blocking NETosis with genetic and chemical inhibition (Aim 2). These studies will advance the field of innate immunity in ocular inflammation, and provide pre-clinical evidence for NETosis as a therapeutic target for drug development of new treatments for patients with uveitis.