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Cell Rep. 2015 Feb 24;10(7):1173-86. doi: 10.1016/j.celrep.2015.01.050. Epub 2015 Feb 19.

ROCK-isoform-specific polarization of macrophages associated with age-related macular degeneration.

Author information

1
Center 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.
2
Center 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, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
3
Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon 406-799, Republic of Korea.
4
Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Transplant Medicine, San Raffaele Hospital, 20132 Milan, Italy.
5
Center 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, the First and Second Affiliated Hospitals of the Harbin Medical University, Harbin 150086, China.
6
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
7
Center 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; State Key Laboratory of Oncology, Minimally Invasive Interventional Division, Medical Imaging Center, Sun Yat-Sen University, Guangzhou 510060, China.
8
Surface Logix, Inc., 50 Soldiers Field Place, Brighton, MA 02135, USA.
9
Center 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.
10
Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
11
Department of Signal Transduction in Tumor Cells, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany.
12
Department of Ophthalmology, School of Medical Sciences, Nihon University, Tokyo 173-8610, Japan.
13
Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
14
Center 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. Electronic address: ahm@bwh.harvard.edu.

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.

PMID:
25704819
PMCID:
PMC5219927
DOI:
10.1016/j.celrep.2015.01.050
[Indexed for MEDLINE]
Free PMC Article

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