Figure 5.

Conceptual summary of the proposed cellular events in aged CXCR5–/– retinas and choroid based on the findings of the current study. (A) CXCR5^−/− microglia cells demonstrated upregulation of Arg-1 in the retina. Increased production of CXCL13-activated microglia cells migrating toward the RPE, releasing COX-2, TNFa, and excessive amounts of Arg-1. RPE and photoreceptor cells were affected by cytokine signaling, triggering cell death. The loss of photoreceptors and subsequent neuronal connections led to reduced MAP-2 signaling within the retina. RPE65 positive cellular debris of dying photoreceptors subjected to phagocytosis by microglia cells and eventually deposited in the sub-RPE space, triggering the accumulation of amyloid beta, Cryaa, Cryab, and other AMD-associated proteins. Constant proinflammatory signaling within the RPE layer affected the tight junction proteins, including ZO-1, compromising the BRB and making drusen components accessible to the immune system and production of specific autoantibodies. The binding of autoantibodies to the components of sub-RPE deposits triggered infiltration with CD4-positive inflammatory cells. Constant VEGF signaling within the choroid led to the release of VEGF-a and choroidal neovascularization. (B) Healthy retina and RPE layers of WT animal.