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Variants near the ATP-binding cassette transporter A1 ( ABCA1 ) gene are associated with elevated intraocular pressure and newly discovered risk factors for glaucoma. Previous studies have shown an association between ABCA1 deficiency and retinal inflammation. Using a mouse model of ischemia-reperfusion (IR) induced by acute intraocular pressure elevation, we found that the retinal expression of ABCA1 protein was decreased. An induction of ABCA1 expression by liver X receptor agonist TO901317 reduced retinal ganglion cell (RGC) apoptosis after IR and promoted membrane translocation and secretion of the anti-inflammatory factor annexin A1 (ANXA1). Moreover, ABCA1 and ANXA1 co-localized in cell membranes, and the interaction domain is amino acid 196 to 274 of ANXA1 fragment. TO901317 also reduced microglia migration and activation and decreased the expression of pro-inflammatory cytokines interleukin (IL)-17A and IL-1β, which could be reversed by the ANXA1 receptor blocker Boc2. Overexpression of TANK-binding kinase 1 ( TBK1 ) increased ABCA1 degradation, which was reversed by the proteasome inhibitor carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG132). Silencing  Tbk1  with siRNA increased ABCA1 expression and promoted ANXA1 membrane translocation. These results indicate a novel IR mechanism, that leads via TBK1 activation to ABCA1 ubiquitination. This degradation decreases ANXA1 secretion, thus facilitating retinal inflammation and RGC apoptosis. Our findings suggest a potential treatment strategy to prevent RGC apoptosis in retinal ischemia and glaucoma.

Reduced Annexin A1 Secretion by ABCA1 Causes Retinal Inflammation and Ganglion Cell Apoptosis in a Murine Glaucoma Model