Fig. 6

Proposed mechanism of systemic LPS-induced retinal microglia activation and retinal dysfunction. A. The inner BRB (iBRB) is composed by a deep, an intermediate, and a superficial vascular plexus. In the healthy retina, endothelial cells, that line the blood vessels, are connected by tight junctions forming an effective vascular barrier. Endothelial cells bear TLR4 receptors and they are surrounded by pericytes and perivascular macrophages. Microglia resides in close proximity to the vasculature, while monocytes circulate in the bloodstream. B. Upon the systemic LPS challenge, LPS binds to TLR4 located on circulating monocytes and endothelial cells (1), and induces the expression of the adhesion molecule ICAM-1 from the latter (2). Activated endothelial cells release cytokines and chemokines (3), which may act as chemoattractants causing microglia migration towards the affected vasculature (4). Subsequently, monocyte-derived macrophages are entering the retina through the disrupted BRB and AIF-1 – ICAM-1 interactions (5). Migration of microglia away from retinal neurons may account for disruption of ribbon synapses and impaired retinal function (6). EC endothelial cell; GCL ganglion cell layer; iBRB inner blood retinal barrier; ICAM-1 intercellular molecule 1; INL inner nuclear layer; IPL inner plexiform layer; LFA-1 lymphocyte function-associated antigen 1; LPS lipopolysaccharide; M microglia; MDMs monocyte-derived macrophages; ONL outer nuclear layer; OPL outer plexiform layer; PRs photoreceptors; PVMs perivascular macrophages; RSs ribbon synapses; TJs tight junctions; TLR4 Toll-like receptor 4