, 2006; Figure 2). Furthermore, oxidative stress of the RPE by photo-oxidation products activates complement Epacadostat (Zhou et al., 2006), and an oxidative damaged-induced autoimmune reaction results in complement deposition in the retina (Hollyfield et al., 2008). Thus, just as the RPE secretes diverse direct effectors of angiogenesis

in response to heterogeneous stressors, there are multiple pathways by which the RPE can regulate the retinal immune-landscape, which in turn can regulate neovascularization in AMD. In particular, in CNV, the macrophage is the king of vascular-modifying immune cells that are attracted to the retina in disease; an increase in the number of retinal macrophages is a hallmark of CNV (Cherepanoff et al., 2010, Grossniklaus et al., 2000 and Skeie and Mullins, 2009; Figure 2). However, whether macrophages are critical

for CNV development or progression is not clear—their increase in CNV could either represent an exacerbation of disease or a compensatory vascular-dampening response. In support of their proangiogenic properties, inhibition of monocyte migration to the retina reduced CNV in a laser-induced mouse model of disease (Espinosa-Heidmann et al., 2003 and Sakurai et al., 2003). In contrast, in a non-injury mouse model of AMD, mice that are genetically deficient for either CCR2 or its cognate ligand (CCL2)—and consequently enough possess defects in Hydroxychloroquine nmr macrophage mobilization—develop choroidal neovascularization (Ambati et al.,

2003b), suggesting that macrophages somehow also protect against CNV (Ambati et al., 2003b and Molday et al., 2000). The reader is directed to an excellent review of the role of macrophages in CNV (Skeie and Mullins, 2009). Given the available evidence, the most likely role for macrophages in CNV is determined by local macrophage-polarizing factors (Kelly et al., 2007 and Patel et al., 2008). Indeed, work in tumor biology has revealed complex local regulation of macrophage vascular-modifying activity. In light of current interest in immune-modulating interventions for CNV (Wang et al., 2011b), the particular microenvironmental influences governing macrophage activity in CNV remains an area of needed research. The potential for immune contribution to CNV begs several salient questions about disease mechanism. For one, if certain proangiogenic factors are also proinflammatory, does antiangiogenesis therapy achieve its clinical effect by reducing both direct vascular and indirect immune effects? Among the many factors that control macrophage chemotaxis, VEGF-A has a well-defined role in recruitment of proangiogenic macrophages (Cursiefen et al., 2004). Therefore, it is reasonable to expect that anti-VEGF therapy might reduce macrophage infiltration of the retina in CNV.