Angiopoietin-like Protein 2 Is a Multistep Regulator of Inflammatory Neovascularization in a Murine Model of Age-related Macular Degeneration

• Published in: The Journal of biological chemistry 2016-04, Vol.291 (14), p.7373-7385
• Main Authors: Hirasawa, Manabu, Takubo, Keiyo, Osada, Hideto, Miyake, Seiji, Toda, Eriko, Endo, Motoyoshi, Umezawa, Kazuo, Tsubota, Kazuo, Oike, Yuichi, Ozawa, Yoko
• Format: Article
• Language: English
• Subjects: age-related macular degeneration; angiopoietin-like protein 2; Angiopoietin-like Proteins; Angiopoietins - biosynthesis; Angiopoietins - genetics; Animals; CD18 Antigens - genetics; CD18 Antigens - metabolism; Cell Line; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; choroidal neovascularization; Choroidal Neovascularization - genetics; Choroidal Neovascularization - metabolism; Choroidal Neovascularization - pathology; Disease Models, Animal; extracellular-signal-regulated kinase (ERK); Humans; inflammation; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Inflammation Mediators - metabolism; inflammatory mediators; integrin; Integrin alpha4 - genetics; Integrin alpha4 - metabolism; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Interleukin-6 - genetics; Interleukin-6 - metabolism; macrophage; Macrophages - metabolism; Macrophages - pathology; Macular Degeneration - genetics; Macular Degeneration - metabolism; Macular Degeneration - pathology; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Mice; migration; Molecular Bases of Disease; NF-kappa B (NF-KB); Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.710186

Choroidal neovascularization (CNV) is a pathogenic process of age-related macular degeneration, a vision-threatening disease. The retinal pigment epithelium and macrophages both influence CNV development. However, the underlying mechanisms remain obscure. Here, we focus on Angptl2 (angiopoietin-like protein 2), a cytokine involved in age-related systemic diseases. Angptl2 was originally identified as an adipocytokine and is also expressed in the eye. Using a laser-induced CNV model, we found that Angptl2 KO mice exhibited suppressed CNV development with reduced macrophage recruitment and inflammatory mediator induction. The mediators monocyte chemotactic protein-1, interleukin-1β (Il-1β), Il-6, matrix metalloprotease-9 (Mmp-9), and transforming growth factor-β1 (Tgf-β1) that were up-regulated during CNV development were all suppressed in the retinal pigment epithelium-choroid of CNV models generated in the Angptl2 KO mice. Bone marrow transplantation using wild-type and KO mice suggested that both bone marrow-derived and host-derived Angptl2 were responsible for macrophage recruitment and CNV development. Peritoneal macrophages derived from Angptl2 KO mice expressed lower levels of the inflammatory mediators. In the wild-type peritoneal macrophages and RAW264.7 cells, Angptl2 induced the mediators via integrins α4 and β2, followed by the downstream activation of NF-κB and ERK. The activation of NF-κB and ERK by Angptl2 also promoted macrophage migration. Therefore, Angptl2 from focal tissue might trigger macrophage recruitment, and that from recruited macrophages might promote expression of inflammatory mediators including Angptl2 in an autocrine and/or paracrine fashion to facilitate CNV development. Angptl2 might therefore represent a multistep regulator of CNV pathogenesis and serve as a new therapeutic target for age-related macular degeneration.