Role of Macrophages

Some studies have suggested that macrophages may play a protective role in AMD, while others suggest that they promote disease progression. Some investigators have suggested that macrophages promote CNV formation. They have shown in the mouse laser-injury model of CNV that depletion of macrophages diminishes the size of the CNV lesions. They have also shown that neovascular AMD patients tend to have higher levels of expression of tumor necrosis factor (TNF)-a in their circulating monocytes than controls. TNF-a is considered a marker for monocyte activation. Others propose that macrophages have a role in preventing AMD. Mice deficient in monocyte chemoattractact protein-1 (also known as CCL-2) or its receptor can develop CNV in old age, suggesting that impaired macrophage recruitment in these mice is responsible for decreased clearance of proinflammatory mediators, such as C5 and IgG, from the sub-RPE tissues, resulting in an increased risk for CNV. This idea is very attractive, but other groups have had difficulty reproducing the results. Mouse studies using the laser model of CNV have shown that IL-10 inhibits recruitment of macrophages into CNV lesions, but this leads to increased CNV size, suggesting that macrophages are antiangiogenic. Additional animal studies propose that senescence may cause a shift in the ocular microenvironment (including higher IL-10 levels) that makes it more proangiogenic; and that microenvironment, in turn, alters the polarization of macrophages toward an M2 phenotype which is unable to regulate angiogenesis. Thus, young macrophages appear to have an antiangiogenic role, while aging M2 macrophages change toward a proangiogenic phenotype. This could explain the different results obtained by different groups using the mouse laser model. Although it is still too early to determine if these conclusions apply to a noninjury model of CNV or to human AMD, the idea that ‘‘not all macrophages are made equal’’ and under different conditions may have opposing roles in AMD is very attractive.

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