Editorial
Macrophages and Macular Degeneration Martine J. Jager, MD, PhD Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands
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 al2 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 hypoxiainducible 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 to massive tumor growth in non-treated eyes and in macrophagedepleted young mice. Macrophage-depleted eyes in old mice on the other hand, no longer developed intraocular tumors.9 Previously, Espinosa-Heidmann et al 10 showed that there was a difference in function between macrophages from old versus young mice: after laser treatment, older mice developed much more angiogenesis and macrophage depletion reduced the amount of blood vessels. Kelly et al11 also used an experimental laser model, in which macrophage depletion was shown to affect the development of choroidal neovascularization (CNV) in old mice, as less vascular scarring was seen after treatment with clodronate-containing liposomes. They also injected splenic macrophages from young as well as old mice into the eyes of old mice on the day of laser treatment and measured CNV seven days later. Macrophages from young mice had an angiogenesis inhibitory role, while macrophages from old mice did not inhibit angiogenesis. One may conclude that macrophages not only play a role in inflammation, but also stimulate
JOURNAL OF OPHTHALMIC AND VISION RESEARCH 2014; Vol. 9, No. 1
1
Editorial; Jager
angiogenesis; two important characteristics of age-related macular degeneration. Influencing the behavior or presence of macrophages may therefore change the local inflammatory process and vessel growth. One may consider interfering with the development of M2 macrophages, or with macrophage chemotaxis. Decreasing the number of macrophages may influence the process of angiogenesis and thereby the development of wet AMD. However, one should always take into account that macrophage depletion also affects M1 macrophages, and antiinfectious activity of the innate immune system. A study on macrophage depletion in corneal Acanthamoeba infection showed that in the absence of macrophages, the immune defense against this parasite was greatly reduced.12 In this issue of JOVR, the authors put forward a very logical hypothesis: a decrease in the presence or activity of M2 macrophages should help block or prevent progression of AMD. The authors injected zoledronic acid into the vitreous of rats to determine whether it had any adverse effect. The idea behind this study is excellent, and although the data should be regarded as preliminary, only limited inflammatory responses were reported. The ERG data show too much variability to draw any conclusions, but indicate the way forward that has to be taken to determine whether oral or local application, for instance through subconjunctival injections, of bisphosphonates is an option for preventive treatment of AMD in high risk patients. REFERENCES 1. Miller JW. Age-related macular degeneration revisited—piecing the puzzle: the LXIX Edward Jackson memorial lecture. Am J Ophthalmol 2013;155:1-35.e13. 2. Nourinia R, Ahmadieh H, Rezaei Kanavi M, Shoeibi N, Kamrava K, Karimi S. Safety of intravitreal
2
Zoledronic acid, an anti-angiogenic bisphosphonate, in a rat model. J Ophthalmic Vis Res 2014;9:44-49. 3. van Furth R, Cohn ZA, Hirsch JG, Humphrey JH, Spector WG, Langevoort HL. The mononuclear phagocyte system: a new classification of macrophages, monocytes, and their precursor cells. Bull World Health Organ 1972;46:845-852. 4. Penfold PL, Madigan MC, Gillies MC, Provis JM. Immunological and aetiological aspects of macular degeneration. Prog Retin Eye Res 2001;20:385-414. 5. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002;23:549-555. 6. Bronkhorst IH, Ly LV, Jordanova ES, Vrolijk J, Versluis M, Luyten GP, et al. Detection of M2macrophages in uveal melanoma and relation with survival. Invest Ophthalmol Vis Sci 2011;52:643-650. 7. Jager MJ, Ly LV, El Filali M, Madigan MC. Macrophages in uveal melanoma and in experimental ocular tumor models: Friends or foes? Prog Retin Eye Res 2011;30:129-146. 8. Toivonen P, Mäkitie T, Kujala E, Kivelä T. Microcirculation and tumor-infiltrating macrophages in choroidal and ciliary body melanoma and corresponding metastases. Invest Ophthalmol Vis Sci 2004;45:1-6. 9. Ly LV, Baghat A, Versluis M, Jordanova ES, Luyten GP, van Rooijen N, et al. In aged mice, outgrowth of intraocular melanoma depends on proangiogenic M2-type macrophages. J Immunol 2010;185:34813488. 10. Espinosa-Heidmann DG, Suner IJ, Hernandez EP, Monroy D, Csaky KG, Cousins SW. Macrophage depletion diminishes lesion size and severity in experimental choroidal neovascularisation. Invest Ophthalmol Vis Sci 2003;44:3586-3592. 11. Kelly J, Ali Khan A, Yin J, Ferguson TA, Apte RS. Senescence regulates macrophage activation and angiogenic fate at sites of tissue injury in mice. J Clin Invest 2007;117:3421-3426. 12. van Klink F, Taylor WM, Alizadeh H, Jager MJ, van Rooijen N, Niederkorn JY. The role of macrophages in Acanthamoeba keratitis. Invest Ophthalmol Vis Sci 1996;37:1271-1281.
JOURNAL OF OPHTHALMIC AND VISION RESEARCH 2014; Vol. 9, No. 1
Macrophages and Macular Degeneration Martine J. Jager, MD, PhD Department of Ophthalmology, Leiden University Medical Center, Leiden, The Netherlands
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 al2 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 hypoxiainducible 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 to massive tumor growth in non-treated eyes and in macrophagedepleted young mice. Macrophage-depleted eyes in old mice on the other hand, no longer developed intraocular tumors.9 Previously, Espinosa-Heidmann et al 10 showed that there was a difference in function between macrophages from old versus young mice: after laser treatment, older mice developed much more angiogenesis and macrophage depletion reduced the amount of blood vessels. Kelly et al11 also used an experimental laser model, in which macrophage depletion was shown to affect the development of choroidal neovascularization (CNV) in old mice, as less vascular scarring was seen after treatment with clodronate-containing liposomes. They also injected splenic macrophages from young as well as old mice into the eyes of old mice on the day of laser treatment and measured CNV seven days later. Macrophages from young mice had an angiogenesis inhibitory role, while macrophages from old mice did not inhibit angiogenesis. One may conclude that macrophages not only play a role in inflammation, but also stimulate
JOURNAL OF OPHTHALMIC AND VISION RESEARCH 2014; Vol. 9, No. 1
1
Editorial; Jager
angiogenesis; two important characteristics of age-related macular degeneration. Influencing the behavior or presence of macrophages may therefore change the local inflammatory process and vessel growth. One may consider interfering with the development of M2 macrophages, or with macrophage chemotaxis. Decreasing the number of macrophages may influence the process of angiogenesis and thereby the development of wet AMD. However, one should always take into account that macrophage depletion also affects M1 macrophages, and antiinfectious activity of the innate immune system. A study on macrophage depletion in corneal Acanthamoeba infection showed that in the absence of macrophages, the immune defense against this parasite was greatly reduced.12 In this issue of JOVR, the authors put forward a very logical hypothesis: a decrease in the presence or activity of M2 macrophages should help block or prevent progression of AMD. The authors injected zoledronic acid into the vitreous of rats to determine whether it had any adverse effect. The idea behind this study is excellent, and although the data should be regarded as preliminary, only limited inflammatory responses were reported. The ERG data show too much variability to draw any conclusions, but indicate the way forward that has to be taken to determine whether oral or local application, for instance through subconjunctival injections, of bisphosphonates is an option for preventive treatment of AMD in high risk patients. REFERENCES 1. Miller JW. Age-related macular degeneration revisited—piecing the puzzle: the LXIX Edward Jackson memorial lecture. Am J Ophthalmol 2013;155:1-35.e13. 2. Nourinia R, Ahmadieh H, Rezaei Kanavi M, Shoeibi N, Kamrava K, Karimi S. Safety of intravitreal
2
Zoledronic acid, an anti-angiogenic bisphosphonate, in a rat model. J Ophthalmic Vis Res 2014;9:44-49. 3. van Furth R, Cohn ZA, Hirsch JG, Humphrey JH, Spector WG, Langevoort HL. The mononuclear phagocyte system: a new classification of macrophages, monocytes, and their precursor cells. Bull World Health Organ 1972;46:845-852. 4. Penfold PL, Madigan MC, Gillies MC, Provis JM. Immunological and aetiological aspects of macular degeneration. Prog Retin Eye Res 2001;20:385-414. 5. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002;23:549-555. 6. Bronkhorst IH, Ly LV, Jordanova ES, Vrolijk J, Versluis M, Luyten GP, et al. Detection of M2macrophages in uveal melanoma and relation with survival. Invest Ophthalmol Vis Sci 2011;52:643-650. 7. Jager MJ, Ly LV, El Filali M, Madigan MC. Macrophages in uveal melanoma and in experimental ocular tumor models: Friends or foes? Prog Retin Eye Res 2011;30:129-146. 8. Toivonen P, Mäkitie T, Kujala E, Kivelä T. Microcirculation and tumor-infiltrating macrophages in choroidal and ciliary body melanoma and corresponding metastases. Invest Ophthalmol Vis Sci 2004;45:1-6. 9. Ly LV, Baghat A, Versluis M, Jordanova ES, Luyten GP, van Rooijen N, et al. In aged mice, outgrowth of intraocular melanoma depends on proangiogenic M2-type macrophages. J Immunol 2010;185:34813488. 10. Espinosa-Heidmann DG, Suner IJ, Hernandez EP, Monroy D, Csaky KG, Cousins SW. Macrophage depletion diminishes lesion size and severity in experimental choroidal neovascularisation. Invest Ophthalmol Vis Sci 2003;44:3586-3592. 11. Kelly J, Ali Khan A, Yin J, Ferguson TA, Apte RS. Senescence regulates macrophage activation and angiogenic fate at sites of tissue injury in mice. J Clin Invest 2007;117:3421-3426. 12. van Klink F, Taylor WM, Alizadeh H, Jager MJ, van Rooijen N, Niederkorn JY. The role of macrophages in Acanthamoeba keratitis. Invest Ophthalmol Vis Sci 1996;37:1271-1281.
JOURNAL OF OPHTHALMIC AND VISION RESEARCH 2014; Vol. 9, No. 1
