Role of S100A9 in diabetic retinopathy

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Diabetic retinopathy (DR) is a microvasculature disease causing irreversible blindness in 50% of working adults with type 2 diabetes mellitus (T2DM). Chronic sterile inflammation is one of the key players involved in DR progression, however no treatment strategy is available for the early inflammatory milieu. S100A9 is a damage-associated molecular patterns (DAMPs) protein found at the injury sites of inflammatory diseases. However, the function of S100A9 in the retina and DR is yet to be studied. This study was designed to characterize S100A9 in the retina and its role in DR pathogenesis. Firstly, S100A9 protein was identified to associate with severity of DR in human patient plasma. In the retina, S100A9 was found upregulated in the retina of Ossabaw pig model of early DR. Obese pigs fed a western diet showed signs of retinal damage including pericyte loss, basement membrane thickening, and neuronal degeneration. S100A9 was increased in the inner and outer plexiform layers of the retina and localized to the activated retinal microglial cells. We then established the culture of primary pig retinal microglial (pMicroglia) cells for further examination of S100A9 mechanism of action in DR. Activated pMicroglia were shown to produce S100A9 protein, which induced pro-inflammatory response via production of IL-1[beta], IL-6 and IL-8. Paquinimod, a Q-compound, inhibited S100A9 binding to TLR4 and thus dampened the pro-inflammatory response via downstream regulation of TLR4 and NLRP3 inflammasome. In conclusion, this study reports microglial-derived S100A9 to be a possible instigator of early damage seen in DR pathogenesis, which can be targeted for therapeutic intervention in human DR patients.