title: ROCK-isoform-specific polarization of macrophages associated with age-related macular degeneration.
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.
authors.affiliation: 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.
authors.forename: Souska
authors.initials: S
authors.lastname: Zandi
authors.affiliation: 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.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nakao
authors.affiliation: Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University, Incheon 406-799, Republic of Korea.
authors.forename: Kwang-Hoon
authors.initials: KH
authors.lastname: Chun
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Transplant Medicine, San Raffaele Hospital, 20132 Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Fiorina
authors.affiliation: 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.
authors.forename: Dawei
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Arita
authors.affiliation: 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.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Surface Logix, Inc., 50 Soldiers Field Place, Brighton, MA 02135, USA.
authors.forename: Enoch
authors.initials: E
authors.lastname: Kim
authors.affiliation: Surface Logix, Inc., 50 Soldiers Field Place, Brighton, MA 02135, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Schueller
authors.affiliation: Surface Logix, Inc., 50 Soldiers Field Place, Brighton, MA 02135, USA.
authors.forename: Stewart
authors.initials: S
authors.lastname: Campbell
authors.affiliation: 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.
authors.forename: Mahdi
authors.initials: M
authors.lastname: Taher
authors.affiliation: 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.
authors.forename: Mark Ivan
authors.initials: MI
authors.lastname: Melhorn
authors.affiliation: 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.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schering
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Transplant Medicine, San Raffaele Hospital, 20132 Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Gatti
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Transplant Medicine, San Raffaele Hospital, 20132 Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Tezza
authors.affiliation: 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.
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.affiliation: Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Transplant Medicine, San Raffaele Hospital, 20132 Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vergani
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Keijiro
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Muneo
authors.initials: M
authors.lastname: Yamaguchi
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Sasaki
authors.affiliation: Department of Signal Transduction in Tumor Cells, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13092 Berlin, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Schmidt-Ullrich
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Hata
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Enaida
authors.affiliation: Department of Ophthalmology, School of Medical Sciences, Nihon University, Tokyo 173-8610, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Yuzawa
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yokomizo
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Young-Bum
authors.initials: YB
authors.lastname: Kim
authors.affiliation: Surface Logix, Inc., 50 Soldiers Field Place, Brighton, MA 02135, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Sweetnam
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Ishibashi
authors.affiliation: 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.
authors.forename: Ali
authors.initials: A
authors.lastname: Hafezi-Moghadam
mesh_terms: D000375:Aging; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000187:drug effects; D016764:Cell Polarity; D002478:Cells, Cultured; D002829:Choroid / Q000098:blood supply; D020256:Choroidal Neovascularization; D016207:Cytokines / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008268:Macular Degeneration / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; C515854:Rock1 protein, mouse; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases