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

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
• Journal: JCI insight (JCI Insight) Vol. 3 Issue 18 (09 20 2018) ISSN: 2379-3708 [Electronic] United States
• PMID: 30232269 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzopyrans
• Carboxylic Acids
• Indoles
• Ltb4r1 protein, mouse
• Ltb4r2 protein, mouse
• Receptors, Leukotriene B4
• MK-886
• Leukotriene B4
• Leucine
• ubenimex
• zileuton
• Hydroxyurea
• CP 105696

Topics

• Animals
• Benzopyrans (pharmacology)
• Carboxylic Acids (pharmacology)
• Choroidal Neovascularization
• Disease Models, Animal
• Eye (radiation effects)
• Eye Injuries
• Hydroxyurea (analogs & derivatives, pharmacology)
• Indoles (pharmacology)
• Lasers (adverse effects)
• Leucine (analogs & derivatives, pharmacology)
• Leukotriene B4 (antagonists & inhibitors, genetics, metabolism)
• Macrophages (drug effects, metabolism)
• Macular Degeneration (metabolism, pathology)
• Male
• Mice
• Mice, Knockout
• Neovascularization, Pathologic (drug therapy, metabolism)
• Receptors, Leukotriene B4 (genetics, metabolism)
• Signal Transduction