Annexin A2 Promotes Epiretinal Membrane Formation and Subsequent Proliferative Vitreoretinopathy in Response to a Macrophage Inflammatory Signal in Mice

Proliferative vitreoretinopathy (PVR) is a chronic, fibrosing, vision-threatening response to retinal injury that occurs in approximately half of individuals with penetrating ocular trauma, as well as in patients with rhegmatogenous retinal detachment or giant retinal tear. Current treatment for this common cause of post-traumatic blindness, remains unsatisfactory. Here, we show for the first time that the PVR reaction is profoundly blunted in a standard model system in annexin A2-deficient mice. We identify a new pathway whereby secretion of macrophage chemokines (macrophage inflammatory proteins, [MIP-1alpha and MIP-1beta]) signal the translocation of annexin A2 from the cytoplasm to the cell surface of retinal pigment epithelial cells (RPEs). Surface expression of A2 enables RPEs to activate surface proteases that allow them to delaminate, migrate to the vitreal surface of the retinal, and begin to secrete epiretinal membrane-forming proteins. RPE cell migration is markedly reduced in the injured retina in annexin A2-deficient mice, and antibody blockade of A2 appears to prevent PVR in wild type mice. We conclude that A2 may be a tractable, intraocular target for the prevention of PVR following eye injury.