Macrophages and Macular Degeneration

Treatment of retinal diseases such as age-related macular degeneration (AMD), macular edema and occlusive vascular disease has benefitted greatly from basic and translational research. Understanding of the role of vascular endothelial growth factor (VEGF) led to the development of its inhibitors, which are now widely applied. 1 In this issue of JOVR, Nourinia et al 2 investigate a potentially new drug that may one day be used to prevent further progression of AMD when started at an early stage. Zoledronic acid belongs to the bisphosphonates, which were originally developed as inhibitors of a specific type of macrophages, the osteoclast, 3 and are being used to treat bone-resorption by bone metastases or prevent osteoporosis. Histologic analysis of eyes at different stages of macular degeneration has shown the presence of macrophages in drusen. 4 But what do macrophages do? Macrophages develop in the bone marrow and circulate as monocytes in the blood stream, until recruited into tissues in response to local chemokine production. One factor may be hypoxia, which is known to lead to monocyte migration. Hypoxia stimulates the production of many factors, such as the transcription factor complexes of hypoxia-inducible factors (HIFs). HIF1 activity promotes the production of a wide range of pro-angiogenic factors, including VEGF-A, and of immune system modifiers, such as MCP-1, TNF-α, each capable of attracting myeloid cells to hypoxic areas. Macrophages have many different functions, but can be separated into at least two main types, namely M1 and M2 macrophages. M1 macrophages play an important role in presenting antigens to the immune system, e.g. stimulating immune responses against infections. M2 macrophages on the other hand show more phagocytic capacity, promote tissue remodelling and are by themselves pro-angiogenic. 5 In uveal melanoma, macrophages have been shown to be related to angiogenesis; the predominant type of infiltrating macrophage is the M2 type. 6,7 An increased macrophage density in uveal melanoma is associated with increased vascular density and a higher chance of developing metastases. 8 As uveal melanoma metastases only develop hematogenously, access of tumor cells to the bloodstream is essential, and this makes it clear why blood vessels are so important. As blood vessels may also be involved in tumor growth, we tried to prevent intraocular tumor growth by macrophage depletion which was achieved by subconjunctival injection of clodronate-containing liposomes; clodronate is also a bisphosphonate. Subsequent injection of murine tumor cells in the anterior chamber of the eye led …