TY - JOUR
T1 - Leukotriene B4 promotes neovascularization and macrophage recruitment in murine wet-type AMD models
AU - Sasaki, Fumiyuki
AU - Koga, Tomoaki
AU - Ohba, Mai
AU - Saeki, Kazuko
AU - Okuno, Toshiaki
AU - Ishikawa, Keijiro
AU - Nakama, Takahito
AU - Nakao, Shintaro
AU - Yoshida, Shigeo
AU - Ishibashi, Tatsuro
AU - Ahmadieh, Hamid
AU - Kanavi, Mozhgan Rezaei
AU - Hafezi-Moghadam, Ali
AU - Penninger, Josef M.
AU - Sonoda, Koh Hei
AU - Yokomizo, Takehiko
N1 - Funding Information:
This work was supported by Grants-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of the Japan Society for the Promotion of Science (JSPS) (grant nos. 22116001, 22116002, 15H05897, 15H05904, 15H04708, and 18H02627 to TY; 25860223, 15K19032, and 17K08664 to TK; 24590386, 15K08316, and 18K06923 to KS; and 25460374, 16K08596, and 15KK0320 to TO) and by grants from the Naito Foundation, the Ono Medical Research Foundation, the Uehara Memorial Foundation, the Mitsubishi Foundation, and the Takeda Science Foundation. This study was supported in part by a Grant-in-Aid (S1311011 to TY) from the Foundation for Strategic Research Projects in Private Universities of the MEXT and by a grant from the Institute for Environmental and Gender-Specific Medicine. We thank the Research Center for Human Disease Modeling (Kyushu University), the Research Support Center of the Division of Molecular and Biochemical Research (Juntendo University), and the Imaging Core Laboratory of the Institute of Medical Science (The University of Tokyo) for technical support. We also thank Eiichi Hasegawa (Harvard Medical School, Boston, Massachusetts, USA) and Akihiko Yoshimura (Keio University, Tokyo, Japan) for technical support of AMD model and BM transplantation, Takako Ichiki (California Institute of Technology, Pasadena, California, USA) for technical support of chemotaxis assay, and Miki Honda (Juntendo University), Akira Matsuda (Juntendo University), and the members of our laboratory for advice and helpful discussion.
Publisher Copyright:
© 2018 American Society for Clinical Investigation. All rights reserved.
PY - 2018/9/20
Y1 - 2018/9/20
N2 - Age-related macular degeneration (AMD), a progressive chronic disease of the central retina, is associated with aging and is a leading cause of blindness worldwide. Here, we demonstrate that leukotriene B4 (LTB4) receptor 1 (BLT1) promotes laser-induced choroidal neovascularization (CNV) in a mouse model for wet-type AMD. CNV was significantly less in BLT1-deficient (BLT1-KO) mice compared with BLT1-WT controls. Expression of several proangiogenic and profibrotic factors was lower in BLT1-KO eyes than in BLT1-WT eyes. LTB4 production in the eyes was substantially increased in the early phase after laser injury. BLT1 was highly expressed in M2 macrophages in vitro and in vivo, and ocular BLT1+ M2 macrophages were increased in the aged eyes after laser injury. Furthermore, M2 macrophages were rapidly attracted by LTB4 and subsequently produced VEGF-A– through BLT1-mediated signaling. Consequently, intravitreal injection of M2 macrophages augmented CNV formation, which was attenuated by BLT1 deficiency. Thus, laser-induced injury to the retina triggered LTB4 production and attracted M2 macrophages via BLT1, leading to development of CNV. A selective BLT1 antagonist (CP105696) and 3 LTB4 inhibitors (zileuton, MK-886, and bestatin) reduced CNV in a dose-dependent manner. CP105696 also inhibited the accumulation of BLT1+ M2 macrophages in the laser-injured eyes of aged mice. Together, these results indicate that the LTB4-BLT1 axis is a potentially novel therapeutic target for CNV of wet-type AMD.
AB - Age-related macular degeneration (AMD), a progressive chronic disease of the central retina, is associated with aging and is a leading cause of blindness worldwide. Here, we demonstrate that leukotriene B4 (LTB4) receptor 1 (BLT1) promotes laser-induced choroidal neovascularization (CNV) in a mouse model for wet-type AMD. CNV was significantly less in BLT1-deficient (BLT1-KO) mice compared with BLT1-WT controls. Expression of several proangiogenic and profibrotic factors was lower in BLT1-KO eyes than in BLT1-WT eyes. LTB4 production in the eyes was substantially increased in the early phase after laser injury. BLT1 was highly expressed in M2 macrophages in vitro and in vivo, and ocular BLT1+ M2 macrophages were increased in the aged eyes after laser injury. Furthermore, M2 macrophages were rapidly attracted by LTB4 and subsequently produced VEGF-A– through BLT1-mediated signaling. Consequently, intravitreal injection of M2 macrophages augmented CNV formation, which was attenuated by BLT1 deficiency. Thus, laser-induced injury to the retina triggered LTB4 production and attracted M2 macrophages via BLT1, leading to development of CNV. A selective BLT1 antagonist (CP105696) and 3 LTB4 inhibitors (zileuton, MK-886, and bestatin) reduced CNV in a dose-dependent manner. CP105696 also inhibited the accumulation of BLT1+ M2 macrophages in the laser-injured eyes of aged mice. Together, these results indicate that the LTB4-BLT1 axis is a potentially novel therapeutic target for CNV of wet-type AMD.
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U2 - 10.1172/JCI.INSIGHT.96902
DO - 10.1172/JCI.INSIGHT.96902
M3 - Article
C2 - 30232269
AN - SCOPUS:85056585292
VL - 3
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 18
M1 - e96902
ER -