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 thatAngptl2KO 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 theAngptl2KO 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 fromAngptl2KO 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.
authors.affiliation: From the Laboratory of Retinal Cell Biology and the Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan, the Department of Ophthalmology, Tokyo Dental College Suidobashi Hospital, Tokyo 101-0061 Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Hirasawa
authors.affiliation: the Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
authors.forename: Keiyo
authors.initials: K
authors.lastname: Takubo
authors.affiliation: From the Laboratory of Retinal Cell Biology and.
authors.forename: Hideto
authors.initials: H
authors.lastname: Osada
authors.affiliation: From the Laboratory of Retinal Cell Biology and.
authors.forename: Seiji
authors.initials: S
authors.lastname: Miyake
authors.affiliation: From the Laboratory of Retinal Cell Biology and.
authors.forename: Eriko
authors.initials: E
authors.lastname: Toda
authors.affiliation: the Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8555, Japan.
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Endo
authors.affiliation: the Department of Molecular Target Medicine Screening, Aichi Medical University School of Medicine, Aichi, 480-1195, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
authors.affiliation: the Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tsubota
authors.affiliation: the Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, 860-8555, Japan, the Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan, and.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
authors.affiliation: From the Laboratory of Retinal Cell Biology and the Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan, ozawa@a5.keio.jp.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ozawa
mesh_terms: D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D018821:CD18 Antigens / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D020256:Choroidal Neovascularization / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D039441:Integrin alpha4 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C485793:Angptl2 protein, mouse; D018821:CD18 Antigens; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C587672:IL1B protein, mouse; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D039441:Integrin alpha4; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: NF-kappa B (NF-KB); age-related macular degeneration; angiopoietin-like protein 2; choroidal neovascularization; extracellular-signal-regulated kinase (ERK); inflammation; inflammatory mediators; integrin; macrophage; migration
references.citation: Br J Ophthalmol. 2014 Sep;98(9):1186-91
references.pmid: 24711658
references.citation: Curr Eye Res. 2004 May;28(5):359-66
references.pmid: 15287373
references.citation: Int J Hematol. 2004 Jul;80(1):21-8
references.pmid: 15293564
references.citation: Mediators Inflamm. 2010;2010. pii: 546826. doi: 10.1155/2010/546826
references.pmid: 20871825
references.citation: Am J Pathol. 2002 Oct;161(4):1247-53
references.pmid: 12368198
references.citation: Biochem Biophys Res Commun. 2013 Jan 18;430(3):1126-31
references.pmid: 23261442
references.citation: Lab Invest. 2012 Nov;92(11):1553-63
references.pmid: 22868908
references.citation: Mediators Inflamm. 2013;2013:435607
references.pmid: 24369445
references.citation: J Clin Invest. 1991 Oct;88(4):1121-7
references.pmid: 1843454
references.citation: Invest Ophthalmol Vis Sci. 2007 May;48(5):2321-6
references.pmid: 17460297
references.citation: Invest Ophthalmol Vis Sci. 2003 Aug;44(8):3578-85
references.pmid: 12882810
references.citation: Am J Pathol. 2010 May;176(5):2309-19
references.pmid: 20304962
references.citation: Invest Ophthalmol Vis Sci. 2007 Sep;48(9):4328-34
references.pmid: 17724224
references.citation: Cancer Res. 2012 Apr 1;72(7):1784-94
references.pmid: 22345152
references.citation: Circ J. 2013;77(9):2311-7
references.pmid: 23739531
references.citation: Invest Ophthalmol Vis Sci. 2013 Nov;54(12):7439-49
references.pmid: 24135751
references.citation: Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2377-82
references.pmid: 23341606
references.citation: Graefes Arch Clin Exp Ophthalmol. 2009 Apr;247(4):515-22
references.pmid: 19048271
references.citation: Arterioscler Thromb Vasc Biol. 2012 Jun;32(6):1400-9
references.pmid: 22556334
references.citation: Arterioscler Thromb Vasc Biol. 2014 Apr;34(4):790-800
references.pmid: 24526691
references.citation: Cell Metab. 2013 Apr 2;17(4):549-61
references.pmid: 23562078
references.citation: Diabetes Care. 2013 Jan;36(1):98-100
references.pmid: 22966088
references.citation: J Clin Invest. 2013 Jul;123(7):2764-72
references.pmid: 23863634
references.citation: Invest Ophthalmol Vis Sci. 2013 Jun;54(6):4278-85
references.pmid: 23702783
references.citation: Invest Ophthalmol Vis Sci. 2007 Dec;48(12):5716-21
references.pmid: 18055824
references.citation: J Biol Chem. 1999 Sep 10;274(37):26523-8
references.pmid: 10473614
references.citation: Mol Cancer Res. 2014 Feb;12(2):239-49
references.pmid: 24258150
references.citation: Sci Signal. 2014 Jan 21;7(309):ra7
references.pmid: 24448647
references.citation: J Mol Cell Cardiol. 2013 Apr;57:1-12
references.pmid: 23333801
references.citation: Nature. 2009 Jul 9;460(7252):225-30
references.pmid: 19525930
references.citation: Cancer Res. 2011 Dec 15;71(24):7502-12
references.pmid: 22042794
references.citation: Am J Pathol. 2007 Jun;170(6):2149-58
references.pmid: 17525280
references.citation: Prog Retin Eye Res. 2010 Nov;29(6):500-19
references.pmid: 20488255
references.citation: Arch Ophthalmol. 2004 Apr;122(4):564-72
references.pmid: 15078675
references.citation: Biochem Biophys Res Commun. 2008 Nov 14;376(2):310-4
references.pmid: 18782563
references.citation: Mol Cancer Res. 2008 Apr;6(4):525-34
references.pmid: 18403633
references.citation: PLoS One. 2014;9(7):e103013
references.pmid: 25048039
references.citation: Curr Pharm Des. 2012;18(1):51-6
references.pmid: 22211688
references.citation: Angiogenesis. 2012 Jun;15(2):213-27
references.pmid: 22392094
references.citation: Invest Ophthalmol Vis Sci. 2001 Oct;42(11):2664-72
references.pmid: 11581214
references.citation: Circ J. 2009 Dec;73(12):2192-7
references.pmid: 19875897
references.citation: J Am Heart Assoc. 2013 Jun;2(3):e000201
references.pmid: 23666461
references.citation: Trans Am Ophthalmol Soc. 2003;101:499-520
references.pmid: 14971591
references.citation: J Cell Sci. 2012 May 15;125(Pt 10):2407-15
references.pmid: 22357958
references.citation: Am J Pathol. 2011 May;178(5):2416-23
references.pmid: 21514452
references.citation: PLoS One. 2013;8(5):e65434
references.pmid: 23741494
references.citation: Biochem Biophys Res Commun. 2013 Jan 18;430(3):981-6
references.pmid: 23261458
references.citation: Invest Ophthalmol Vis Sci. 1994 Jul;35(8):3178-88
references.pmid: 7519180
references.citation: Mol Vis. 2002 Apr 21;8:119-26
references.pmid: 11979237
references.citation: Nat Med. 2003 Nov;9(11):1390-7
references.pmid: 14566334
references.citation: Nat Med. 2012 May;18(5):791-8
references.pmid: 22484808
references.citation: Cell Metab. 2009 Sep;10(3):178-88
references.pmid: 19723494
references.citation: Invest Ophthalmol Vis Sci. 2003 Aug;44(8):3586-92
references.pmid: 12882811
references.citation: Invest Ophthalmol Vis Sci. 2011 Sep;52(10):7213-20
references.pmid: 21813636
references.citation: Am J Ophthalmol. 1999 Jul;128(1):45-53
references.pmid: 10482093
references.citation: Exp Ther Med. 2013 Jun;5(6):1631-1636
references.pmid: 23837045