Angiopoietin-like protein 2 is a multistep regulator of inflammatory neovascularization in a murine model of age-related macular degeneration

Manabu Hirasawa, Keiyo Takubo, Hideto Osada, Seiji Miyake, Eriko Toda, Motoyoshi Endo, Kazuo Umezawa, Kazuo Tsubota, Yuichi Oike, Yoko Ozawa

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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 upregulated 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.

Original languageEnglish
Pages (from-to)7373-7385
Number of pages13
JournalJournal of Biological Chemistry
Volume291
Issue number14
DOIs
Publication statusPublished - 2016 Apr 1

Fingerprint

Angiopoietins
Choroidal Neovascularization
Macular Degeneration
Macrophages
Proteins
Retinal Pigment Epithelium
Peritoneal Macrophages
Retinal Pigments
Bone
Chemical activation
Adipokines
Chemokine CCL2
Transforming Growth Factors
Metalloproteases
Bone Marrow Transplantation
Interleukin-1
Integrins
Lasers
Bone Marrow

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Angiopoietin-like protein 2 is a multistep regulator of inflammatory neovascularization in a murine model of age-related macular degeneration. / Hirasawa, Manabu; Takubo, Keiyo; Osada, Hideto; Miyake, Seiji; Toda, Eriko; Endo, Motoyoshi; Umezawa, Kazuo; Tsubota, Kazuo; Oike, Yuichi; Ozawa, Yoko.

In: Journal of Biological Chemistry, Vol. 291, No. 14, 01.04.2016, p. 7373-7385.

Research output: Contribution to journalArticle

Hirasawa, Manabu ; Takubo, Keiyo ; Osada, Hideto ; Miyake, Seiji ; Toda, Eriko ; Endo, Motoyoshi ; Umezawa, Kazuo ; Tsubota, Kazuo ; Oike, Yuichi ; Ozawa, Yoko. / Angiopoietin-like protein 2 is a multistep regulator of inflammatory neovascularization in a murine model of age-related macular degeneration. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 14. pp. 7373-7385.
@article{2800179e591c461cba9aded0a11c4559,
title = "Angiopoietin-like protein 2 is a multistep regulator of inflammatory neovascularization in a murine model of age-related macular degeneration",
abstract = "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 upregulated 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.",
author = "Manabu Hirasawa and Keiyo Takubo and Hideto Osada and Seiji Miyake and Eriko Toda and Motoyoshi Endo and Kazuo Umezawa and Kazuo Tsubota and Yuichi Oike and Yoko Ozawa",
year = "2016",
month = "4",
day = "1",
doi = "10.1074/jbc.M115.710186",
language = "English",
volume = "291",
pages = "7373--7385",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "14",

}

TY - JOUR

T1 - Angiopoietin-like protein 2 is a multistep regulator of inflammatory neovascularization in a murine model of age-related macular degeneration

AU - Hirasawa, Manabu

AU - Takubo, Keiyo

AU - Osada, Hideto

AU - Miyake, Seiji

AU - Toda, Eriko

AU - Endo, Motoyoshi

AU - Umezawa, Kazuo

AU - Tsubota, Kazuo

AU - Oike, Yuichi

AU - Ozawa, Yoko

PY - 2016/4/1

Y1 - 2016/4/1

N2 - 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 upregulated 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.

AB - 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 upregulated 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.

UR - http://www.scopus.com/inward/record.url?scp=84964837802&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964837802&partnerID=8YFLogxK

U2 - 10.1074/jbc.M115.710186

DO - 10.1074/jbc.M115.710186

M3 - Article

C2 - 26839315

AN - SCOPUS:84964837802

VL - 291

SP - 7373

EP - 7385

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 14

ER -