Cell Reports (Feb 2015)
ROCK-Isoform-Specific Polarization of Macrophages Associated with Age-Related Macular Degeneration
- Souska Zandi,
- Shintaro Nakao,
- Kwang-Hoon Chun,
- Paolo Fiorina,
- Dawei Sun,
- Ryoichi Arita,
- Ming Zhao,
- Enoch Kim,
- Olivier Schueller,
- Stewart Campbell,
- Mahdi Taher,
- Mark Ivan Melhorn,
- Alexander Schering,
- Francesca Gatti,
- Sara Tezza,
- Fang Xie,
- Andrea Vergani,
- Shigeo Yoshida,
- Keijiro Ishikawa,
- Muneo Yamaguchi,
- Fumiyuki Sasaki,
- Ruth Schmidt-Ullrich,
- Yasuaki Hata,
- Hiroshi Enaida,
- Mitsuko Yuzawa,
- Takehiko Yokomizo,
- Young-Bum Kim,
- Paul Sweetnam,
- Tatsuro Ishibashi,
- Ali Hafezi-Moghadam
Affiliations
- Souska Zandi
- Center for Excellence in Functional and Molecular Imaging, Brigham & Women’s Hospital, Boston, MA 02115, USA
- Shintaro Nakao
- Center for Excellence in Functional and Molecular Imaging, Brigham & Women’s Hospital, Boston, MA 02115, USA
- Kwang-Hoon Chun
- Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon 406-799, Republic of Korea
- Paolo Fiorina
- Nephrology Division, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Dawei Sun
- Center for Excellence in Functional and Molecular Imaging, Brigham & Women’s Hospital, Boston, MA 02115, USA
- Ryoichi Arita
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
- Ming Zhao
- Center for Excellence in Functional and Molecular Imaging, Brigham & Women’s Hospital, Boston, MA 02115, USA
- Enoch Kim
- Surface Logix, Inc., 50 Soldiers Field Place, Brighton, MA 02135, USA
- Olivier Schueller
- Surface Logix, Inc., 50 Soldiers Field Place, Brighton, MA 02135, USA
- Stewart Campbell
- Surface Logix, Inc., 50 Soldiers Field Place, Brighton, MA 02135, USA
- Mahdi Taher
- Center for Excellence in Functional and Molecular Imaging, Brigham & Women’s Hospital, Boston, MA 02115, USA
- Mark Ivan Melhorn
- Center for Excellence in Functional and Molecular Imaging, Brigham & Women’s Hospital, Boston, MA 02115, USA
- Alexander Schering
- Center for Excellence in Functional and Molecular Imaging, Brigham & Women’s Hospital, Boston, MA 02115, USA
- Francesca Gatti
- Nephrology Division, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Sara Tezza
- Nephrology Division, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Fang Xie
- Center for Excellence in Functional and Molecular Imaging, Brigham & Women’s Hospital, Boston, MA 02115, USA
- Andrea Vergani
- Nephrology Division, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
- Shigeo Yoshida
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
- Keijiro Ishikawa
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
- Muneo Yamaguchi
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
- Fumiyuki Sasaki
- Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan
- Ruth Schmidt-Ullrich
- Department of Signal Transduction in Tumor Cells, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany
- Yasuaki Hata
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
- Hiroshi Enaida
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
- Mitsuko Yuzawa
- Department of Ophthalmology, School of Medical Sciences, Nihon University, Tokyo 173-8610, Japan
- Takehiko Yokomizo
- Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan
- Young-Bum Kim
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA
- Paul Sweetnam
- Surface Logix, Inc., 50 Soldiers Field Place, Brighton, MA 02135, USA
- Tatsuro Ishibashi
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
- Ali Hafezi-Moghadam
- Center for Excellence in Functional and Molecular Imaging, Brigham & Women’s Hospital, Boston, MA 02115, USA
- DOI
- https://doi.org/10.1016/j.celrep.2015.01.050
- Journal volume & issue
-
Vol. 10,
no. 7
pp. 1173 – 1186
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.
