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

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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

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    Sasaki, F., Koga, T., Ohba, M., Saeki, K., Okuno, T., Ishikawa, K., Nakama, T., Nakao, S., Yoshida, S., Ishibashi, T., Ahmadieh, H., Kanavi, M. R., Hafezi-Moghadam, A., Penninger, J. M., Sonoda, K. H., & Yokomizo, T. (2018). Leukotriene B4 promotes neovascularization and macrophage recruitment in murine wet-type AMD models. JCI Insight, 3(18). https://doi.org/10.1172/jci.insight.96902