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ROCK-isoform-specific polarization of macrophages associated with age-related macular degeneration
Souska Zandi1, Shintaro Nakao2, Kwang-Hoon Chun3
1Center for Excellence in Functional and Molecular Imaging, Brigham & Women's Hospital, Boston, MA 02115, USA; Department of Radiology, Harvard Medical School, Boston, MA 02115, USA; Angiogenesis Laboratory, Massachusetts Eye & Ear Infirmary, Boston, MA 02114, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA; Department of Ophthalmology, Swiss Eye Institute, Rotkreuz and Berner Augenklinik am Lindenhofspital, 3012 Bern, Switzerland.
Abstract:
Age is a major risk factor in age-related macular degeneration (AMD), but the underlying cause is unknown. We find increased Rho-associated kinase (ROCK) signaling and M2 characteristics in eyes of aged mice, revealing immune changes in aging. ROCK isoforms determine macrophage polarization into M1 and M2 subtypes. M2-like macrophages accumulated in AMD, but not in normal eyes, suggesting that these macrophages may be linked to macular degeneration. M2 macrophages injected into the mouse eye exacerbated choroidal neovascular lesions, while M1 macrophages ameliorated them, supporting a causal role for macrophage subtypes in AMD. Selective ROCK2 inhibition with a small molecule decreased M2-like macrophages and choroidal neovascularization. ROCK2 inhibition upregulated M1 markers without affecting macrophage recruitment, underlining the plasticity of these macrophages. These results reveal age-induced innate immune imbalance as underlying AMD pathogenesis. Targeting macrophage plasticity opens up new possibilities for more effective AMD treatment.
Insights
Aging eyes show altered immune cells, specifically M2 macrophages, linked to age-related macular degeneration (AMD). Targeting Rho-associated kinase (ROCK) pathways may restore immune balance and treat AMD.
Area of Science:
- Immunology
- Ophthalmology
- Aging Research
Background:
- Age is a primary risk factor for age-related macular degeneration (AMD).
- The specific immune mechanisms driving AMD pathogenesis remain unclear.
- Rho-associated kinase (ROCK) signaling is implicated in immune cell regulation.
Purpose of the Study:
- To investigate the role of immune changes, specifically macrophage polarization, in age-related macular degeneration (AMD).
- To explore the involvement of Rho-associated kinase (ROCK) signaling in age-related immune dysregulation and AMD.
- To evaluate the therapeutic potential of targeting ROCK signaling for AMD treatment.
Main Methods:
- Analysis of immune cell characteristics, particularly macrophage subtypes (M1 and M2), in aged mouse eyes.
- Assessment of Rho-associated kinase (ROCK) isoform activity and its influence on macrophage polarization.
- Experimental manipulation of macrophage subtypes in vivo to determine their effect on choroidal neovascularization (CNV) in a mouse model.
- Pharmacological inhibition of ROCK2 to assess its impact on M2 macrophages and CNV.
Main Results:
- Aged mouse eyes exhibited increased Rho-associated kinase (ROCK) signaling and M2 macrophage characteristics, indicative of immune alterations.
- M2-like macrophages were found to accumulate in AMD models but not in normal aging eyes.
- In vivo studies demonstrated that M2 macrophages exacerbated choroidal neovascular lesions, while M1 macrophages ameliorated them.
- Selective inhibition of ROCK2 reduced M2-like macrophages and choroidal neovascularization, while upregulating M1 markers.
Conclusions:
- Age-induced innate immune imbalance, characterized by M2 macrophage accumulation, contributes to the pathogenesis of age-related macular degeneration (AMD).
- Macrophage plasticity, regulated by ROCK signaling, is a critical factor in AMD.
- Targeting ROCK2 and modulating macrophage polarization presents a promising therapeutic strategy for AMD.
