For a long time, macrophage-derived VEGF-A was thought to be an important factor for inflammation-driven angiogenesis in CNV.
26–28 Interestingly, using several myeloid-specific VEGF-A knockout models, a recent report proved that myeloid-derived VEGF-A production does not contribute significantly to CNV and vascular leakage.
43 Based on this controversy, myeloid-derived PlGF might be a better candidate to take into account for this role.
44–46 Mononuclear phagocytes in the retina represent a very heterogeneous and dynamic cell type. Different stimuli polarize such cells, altering the gene expression of surface markers and cytokines.
47 Differences in the expression profile are used to classify MPs into the so-called M1 or M2 polarized groups, although this classification has been controversially discussed for years since there is no clear evidence of functional implications. Several lines of evidence have highlighted that M1 macrophages are associated more with residential MPs whereas M2 are recruited (e.g., bone marrow-derived).
48 There is a consensus that M2, the proangiogenic type of macrophages, support neovascularization in laser-induced CNV.
44,49 Among other factors, it has been shown that PlGF upregulation promotes polarization toward M2.
45 PlGF-positive subsets of immune cells detected in the subretinal space might be involved in polarization processes since they are observed only after laser. It is important to note that the dynamics of M1–M2 polarization in the early inflammatory phase of CNV have not yet been extensively described. A recent work by Yang and colleagues
49 has partly characterized these dynamics by means of qPCR, using a more intensive laser CNV model than ours. M1 macrophages were associated more with the early phase of CNV whereas M2 were, in general, predominant in the later phase. Our findings regarding M1 are very similar, although we found differences in M2 marker dynamics, most likely due to the usage of the much milder laser model (4 laser impacts versus 10 impacts). The lower levels of M2 markers in our scenario might be explained by lower levels of recruited immune cells.