TY - JOUR
T1 - ROCK-Isoform-Specific Polarization of Macrophages Associated with Age-Related Macular Degeneration
AU - Zandi, Souska
AU - Nakao, Shintaro
AU - Chun, Kwang Hoon
AU - Fiorina, Paolo
AU - Sun, Dawei
AU - Arita, Ryoichi
AU - Zhao, Ming
AU - Kim, Enoch
AU - Schueller, Olivier
AU - Campbell, Stewart
AU - Taher, Mahdi
AU - Melhorn, Mark Ivan
AU - Schering, Alexander
AU - Gatti, Francesca
AU - Tezza, Sara
AU - Xie, Fang
AU - Vergani, Andrea
AU - Yoshida, Shigeo
AU - Ishikawa, Keijiro
AU - Yamaguchi, Muneo
AU - Sasaki, Fumiyuki
AU - Schmidt-Ullrich, Ruth
AU - Hata, Yasuaki
AU - Enaida, Hiroshi
AU - Yuzawa, Mitsuko
AU - Yokomizo, Takehiko
AU - Kim, Young Bum
AU - Sweetnam, Paul
AU - Ishibashi, Tatsuro
AU - Hafezi-Moghadam, Ali
N1 - Publisher Copyright:
© 2015 The Authors.
PY - 2015/2/24
Y1 - 2015/2/24
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2015.01.050
DO - 10.1016/j.celrep.2015.01.050
M3 - Article
C2 - 25704819
AN - SCOPUS:84924591524
SN - 2211-1247
VL - 10
SP - 1173
EP - 1186
JO - Cell Reports
JF - Cell Reports
IS - 7
ER -