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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
JournalJCI Insight
Volume3
Issue number18
DOIs
Publication statusPublished - Sep 20 2018

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Choroidal Neovascularization
Leukotriene B4
Macular Degeneration
Macrophages
Lasers
L 663536
zileuton
Retina
Wounds and Injuries
Leukotriene B4 Receptors
Intravitreal Injections
Blindness
Vascular Endothelial Growth Factor A
Chronic Disease

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Leukotriene B4 promotes neovascularization and macrophage recruitment in murine wet-type AMD models. / Sasaki, Fumiyuki; Koga, Tomoaki; Ohba, Mai; Saeki, Kazuko; Okuno, Toshiaki; Ishikawa, Keijiro; Nakama, Takahito; Nakao, Shintaro; Yoshida, Shigeo; Ishibashi, Tatsuro; Ahmadieh, Hamid; Kanavi, Mozhgan Rezaei; Hafezi-Moghadam, Ali; Penninger, Josef M.; Sonoda, Koh Hei; Yokomizo, Takehiko.

In: JCI Insight, Vol. 3, No. 18, 20.09.2018.

Research output: Contribution to journalArticle

Sasaki, F, Koga, T, Ohba, M, Saeki, K, Okuno, T, Ishikawa, K, Nakama, T, Nakao, S, Yoshida, S, Ishibashi, T, Ahmadieh, H, Kanavi, MR, Hafezi-Moghadam, A, Penninger, JM, Sonoda, KH & Yokomizo, T 2018, 'Leukotriene B4 promotes neovascularization and macrophage recruitment in murine wet-type AMD models', JCI Insight, vol. 3, no. 18. https://doi.org/10.1172/jci.insight.96902
Sasaki, Fumiyuki ; Koga, Tomoaki ; Ohba, Mai ; Saeki, Kazuko ; Okuno, Toshiaki ; Ishikawa, Keijiro ; Nakama, Takahito ; Nakao, Shintaro ; Yoshida, Shigeo ; Ishibashi, Tatsuro ; Ahmadieh, Hamid ; Kanavi, Mozhgan Rezaei ; Hafezi-Moghadam, Ali ; Penninger, Josef M. ; Sonoda, Koh Hei ; Yokomizo, Takehiko. / Leukotriene B4 promotes neovascularization and macrophage recruitment in murine wet-type AMD models. In: JCI Insight. 2018 ; Vol. 3, No. 18.
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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.",
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AU - Okuno, Toshiaki

AU - Ishikawa, Keijiro

AU - Nakama, Takahito

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AU - Yoshida, Shigeo

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AU - Ahmadieh, Hamid

AU - Kanavi, Mozhgan Rezaei

AU - Hafezi-Moghadam, Ali

AU - Penninger, Josef M.

AU - Sonoda, Koh Hei

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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.

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