ROCK-Isoform-Specific Polarization of Macrophages Associated with Age-Related Macular Degeneration

被引：168

作者：

Zandi, Souska ^{[1
,2
,3
,4
,5
]}

Nakao, Shintaro ^{[1
,2
,3
,4
,6
]}

Chun, Kwang-Hoon ^{[7
]}

Fiorina, Paolo ^{[8
,9
]}

Sun, Dawei ^{[1
,2
,3
,4
,10
,11
]}

Arita, Ryoichi ^{[6
]}

Zhao, Ming ^{[1
,2
,12
]}

Kim, Enoch ^{[13
]}

Schueller, Olivier ^{[13
]}

Campbell, Stewart ^{[13
]}

Taher, Mahdi ^{[1
,2
,3
,4
]}

Melhorn, Mark Ivan ^{[1
,2
,3
,4
]}

Schering, Alexander ^{[1
,2
,3
,4
]}

Gatti, Francesca ^{[8
,9
]}

Tezza, Sara ^{[8
,9
]}

Xie, Fang ^{[1
,2
,3
,4
,10
,11
]}

Vergani, Andrea ^{[8
,9
]}

Yoshida, Shigeo ^{[6
]}

Ishikawa, Keijiro ^{[6
]}

Yamaguchi, Muneo ^{[6
]}

Sasaki, Fumiyuki ^{[14
]}

Schmidt-Ullrich, Ruth ^{[15
]}

Hata, Yasuaki ^{[6
]}

Enaida, Hiroshi ^{[6
]}

Yuzawa, Mitsuko ^{[16
]}

Yokomizo, Takehiko ^{[14
]}

Kim, Young-Bum ^{[17
,18
]}

Sweetnam, Paul ^{[13
]}

Ishibashi, Tatsuro ^{[6
]}

Hafezi-Moghadam, Ali ^{[1
,2
,3
,4
]}

机构：

[1] Brigham & Womens Hosp, Ctr Excellence Funct & Mol Imaging, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA

[3] Massachusetts Eye & Ear Infirm, Angiogenesis Lab, Boston, MA 02114 USA

[4] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02115 USA

[5] Rotkreuz & Berner Augenklin Lindenhofspital, Swiss Eye Inst, Dept Ophthalmol, CH-3012 Bern, Switzerland

[6] Kyushu Univ, Grad Sch Med Sci, Dept Ophthalmol, Fukuoka 8128582, Japan

[7] Gachon Univ, Coll Pharm, Gachon Inst Pharmaceut Sci, Inchon 406799, South Korea

[8] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Nephrol, Boston, MA 02115 USA

[9] Hosp San Raffaele, Div Transplant Med, I-20132 Milan, Italy

[10] Harbin Med Univ, Affiliated Hosp 1, Dept Ophthalmol, Harbin 150086, Peoples R China

[11] Harbin Med Univ, Affiliated Hosp 2, Dept Ophthalmol, Harbin 150086, Peoples R China

[12] Sun Yat Sen Univ, Med Imaging Ctr, Minimally Invas Intervent Div, State Key Lab Oncol, Guangzhou 510060, Peoples R China

[13] Surface Logix Inc, Brighton, MA 02135 USA

[14] Juntendo Univ, Sch Med, Dept Biochem, Tokyo 1138421, Japan

[15] Max Delbruck Ctr Mol Med, Dept Signal Transduct Tumor Cells, D-13092 Berlin, Germany

[16] Nihon Univ, Sch Med Sci, Dept Ophthalmol, Tokyo 1738610, Japan

[17] Beth Israel Deaconess Med Ctr, Div Endocrinol Diabet & Metab, Boston, MA 02115 USA

[18] Harvard Univ, Sch Med, Boston, MA 02115 USA

来源：

CELL REPORTS | 2015年 / 10卷 / 07期

关键词：

NF-KAPPA-B; CARDIAC-HYPERTROPHY; IN-VIVO; MICE; NEOVASCULARIZATION; ACTIVATION; DAMAGE; REQUIREMENT; THERAPY; CELLS;

D O I：

10.1016/j.celrep.2015.01.050

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1173 / 1186

页数：14

共 30 条

[1] Macrophages inhibit neovascularization in a murine model of age-related macular degeneration [J].