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Leukotriene B4 promotes neovascularization and macrophage recruitment in murine wet-type AMD models
Fumiyuki Sasaki, … , Koh-Hei Sonoda, Takehiko Yokomizo
Fumiyuki Sasaki, … , Koh-Hei Sonoda, Takehiko Yokomizo
Published September 20, 2018
Citation Information: JCI Insight. 2018;3(18):e96902. https://doi.org/10.1172/jci.insight.96902.
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Research Article Angiogenesis Inflammation

Leukotriene B4 promotes neovascularization and macrophage recruitment in murine wet-type AMD models

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Abstract

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.

Authors

Fumiyuki Sasaki, Tomoaki Koga, Mai Ohba, Kazuko Saeki, Toshiaki Okuno, Keijiro Ishikawa, Takahito Nakama, Shintaro Nakao, Shigeo Yoshida, Tatsuro Ishibashi, Hamid Ahmadieh, Mozhgan Rezaei Kanavi, Ali Hafezi-Moghadam, Josef M. Penninger, Koh-Hei Sonoda, Takehiko Yokomizo

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Figure 1

BLT1 deficiency attenuates CNV in a mouse model of AMD.

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BLT1 deficiency attenuates CNV in a mouse model of AMD.
Images of isolec...
Images of isolectin B4 (iB4) staining (A) and CNV volume (B) in the RPE-choroid complex from the eyes of BLT1-WT (open circles) and BLT1-KO (filled circles) mice after laser-induced injury. Green represents a CNV area positive for iB4 staining. Mice were grouped by age: young, 8–12 weeks old; middle-aged, 20–24 weeks old; old, 40–48 weeks old. n = 5–6 mice per group. (C and D) Images of H&E staining (C) and CNV lesion area (D). H&E staining of the uninjured and laser-injured retinas from aged BLT1-WT and BLT1-KO mice (>40 weeks old). Yellow dotted lines denote the lesion areas. n = 4–5 per group. Scale bar: 100 μm (A and C). (B and D) *P < 0.05; **P < 0.01 (1-way ANOVA with Bonferroni’s post hoc test [B] and Student’s t test [D]). Results are representative of at least 2 independent experiments.

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