ROCK-isoform-specific polarization of macrophages associated with age-related macular degeneration.
ROCK-isoform-specific polarization of macrophages associated with age-related macular degeneration.
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DOI：
10.1016/j.celrep.2015.01.050
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发表时间：
2015-02-24
期刊：
影响因子：
8.8
通讯作者：
Hafezi-Moghadam A
中科院分区：
文献类型：
--
作者：
Zandi S;Nakao S;Chun KH;Fiorina P;Sun D;Arita R;Zhao M;Kim E;Schueller O;Campbell S;Taher M;Melhorn MI;Schering A;Gatti F;Tezza S;Xie F;Vergani A;Yoshida S;Ishikawa K;Yamaguchi M;Sasaki F;Schmidt-Ullrich R;Hata Y;Enaida H;Yuzawa M;Yokomizo T;Kim YB;Sweetnam P;Ishibashi T;Hafezi-Moghadam A
年龄是年龄相关性黄斑变性（AMD）的主要危险因素，但其根本原因尚不清楚。我们发现老年小鼠眼睛中Rho相关激酶（ROCK）信号和M2特征增加，揭示了衰老中的免疫变化。ROCK亚型决定巨噬细胞极化为M1和M2亚型。M2样巨噬细胞在AMD中积累，但在正常眼中没有，这表明这些巨噬细胞可能与黄斑变性有关。M2巨噬细胞注射到小鼠眼中加重脉络膜新生血管病变，而M1巨噬细胞改善它们，支持AMD中巨噬细胞亚型的因果作用。用小分子选择性ROCK 2抑制减少了M2样巨噬细胞和脉络膜新生血管形成。ROCK2抑制上调M1标志物而不影响巨噬细胞募集，强调了这些巨噬细胞的可塑性。这些结果揭示了年龄诱导的先天免疫失衡作为AMD发病机制的基础。靶向巨噬细胞可塑性为更有效的AMD治疗开辟了新的可能性。
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 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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影响因子：
15.8
作者：
Apte, Rajendra S.;Richter, Jennifer;Herndon, John;Ferguson, Thomas A.
通讯作者：
Ferguson, Thomas A.
影响因子：
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作者：
Takeda, Atsunobu;Baffi, Judit Z.;Kleinman, Mark E.;Cho, Won Gil;Nozaki, Miho;Yamada, Kiyoshi;Kaneko, Hiroki;Albuquerque, Romulo J. C.;Dridi, Sami;Saito, Kuniharu;Raisler, Brian J.;Budd, Steven J.;Geisen, Pete;Munitz, Ariel;Ambati, Balamurali K.;Green, Martha G.;Ishibashi, Tatsuro;Wright, John D.;Humbles, Alison A.;Gerard, Craig J.;Ogura, Yuichiro;Pan, Yuzhen;Smith, Justine R.;Grisanti, Salvatore;Hartnett, M. Elizabeth;Rothenberg, Marc E.;Ambati, Jayakrishna
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Ambati, Jayakrishna
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20.1
作者：
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通讯作者：
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影响因子：
20.3
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Volpert, Olga V.
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