title: IL-4 regulates specific Arg-1(+) macrophage sFlt-1-mediated inhibition of angiogenesis.
abstract: One of the main drivers for neovascularization in age-related macular degeneration is activation of innate immunity in the presence of macrophages. Here, we demonstrate that T helper cell type 2 cytokines and, in particular, IL-4 condition human and murine monocyte phenotype toward Arg-1(+), and their subsequent behavior limits angiogenesis by increasing soluble fms-like tyrosine kinase 1 (sFlt-1) gene expression. We document that T helper cell type 2 cytokine-conditioned murine macrophages neutralize vascular endothelial growth factor-mediated endothelial cell proliferation (human umbilical vein endothelial cell and choroidal vasculature) in a sFlt-1-dependent manner. We demonstrate that in vivo intravitreal administration of IL-4 attenuates laser-induced choroidal neovascularization (L-CNV) due to specific IL-4 conditioning of macrophages. IL-4 induces the expression of sFlt-1 by resident CD11b(+) retinal microglia and infiltrating myeloid cells but not from retinal pigment epithelium. IL-4-induced suppression of L-CNV is not prevented when sFlt-1 expression is attenuated in retinal pigment epithelium. IL-4-mediated suppression of L-CNV was abrogated in IL-4R-deficient mice and in bone marrow chimeras reconstituted with myeloid cells that had undergone lentiviral-mediated shRNA silencing of sFlt-1, demonstrating the critical role of this cell population. Together, these data establish how lL-4 directly drives macrophage sFlt-1 production expressing an Arg-1(+) phenotype and support the therapeutic potential of targeted IL-4 conditioning within the tissue to regulate disease conditions such as neovascular age-related macular degeneration.
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Wei-Kang
authors.initials: WK
authors.lastname: Wu
authors.affiliation: Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Anastasios
authors.initials: A
authors.lastname: Georgiadis
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Copland
authors.affiliation: Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Sidath
authors.initials: S
authors.lastname: Liyanage
authors.affiliation: Institute of Ophthalmology, University College London, London, United Kingdom.
authors.forename: Ulrich F O
authors.initials: UF
authors.lastname: Luhmann
authors.affiliation: Institute of Ophthalmology, University College London, London, United Kingdom; National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital and University College London Institute of Ophthalmology, London, United Kingdom.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Robbie
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Jiahui
authors.initials: J
authors.lastname: Wu
authors.affiliation: Institute of Ophthalmology, University College London, London, United Kingdom; National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital and University College London Institute of Ophthalmology, London, United Kingdom.
authors.forename: James W
authors.initials: JW
authors.lastname: Bainbridge
authors.affiliation: Cancer Biology, Division of Cancer and Stem Cells, School of Medicine, Queen's Medical Centre, The University of Nottingham, Nottingham, United Kingdom.
authors.forename: David O
authors.initials: DO
authors.lastname: Bates
authors.affiliation: Institute of Ophthalmology, University College London, London, United Kingdom; National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital and University College London Institute of Ophthalmology, London, United Kingdom.
authors.forename: Robin R
authors.initials: RR
authors.lastname: Ali
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom; School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Lindsay B
authors.initials: LB
authors.lastname: Nicholson
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom; Institute of Ophthalmology, University College London, London, United Kingdom; School of Clinical Sciences, University of Bristol, Bristol, United Kingdom; National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital and University College London Institute of Ophthalmology, London, United Kingdom. Electronic address: a.dick@bristol.ac.uk.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Dick
mesh_terms: D000818:Animals; D001119:Arginase / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D020256:Choroidal Neovascularization / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
chemical_list: D018793:Interleukin-13; D042461:Vascular Endothelial Growth Factor A; D015847:Interleukin-4; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; C574619:ARG1 protein, human; D001119:Arginase