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IL-4 Regulates Specific Arg-1+ Macrophage sFlt-1–Mediated Inhibition of Angiogenesis

Wu, Wei-Kang; Georgiadis, Anastasios; Copland, David A.; Liyanage, Sidath; Luhmann, Ulrich F.O.; Robbie, Scott J.; Liu, Jian; Wu, Jiahui; Bainbridge, James W.; Bates, David O.; Ali, Robin R.; Nicholson, Lindsay B.; Dick, Andrew D.


Wei-Kang Wu

Anastasios Georgiadis

David A. Copland

Sidath Liyanage

Ulrich F.O. Luhmann

Scott J. Robbie

Jian Liu

Jiahui Wu

James W. Bainbridge

Professor of Oncology

Robin R. Ali

Lindsay B. Nicholson

Andrew D. Dick


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.

Journal Article Type Article
Acceptance Date Apr 4, 2015
Online Publication Date Jun 13, 2015
Publication Date 2015-08
Deposit Date May 20, 2019
Journal The American Journal of Pathology
Print ISSN 0002-9440
Electronic ISSN 1525-2191
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 185
Issue 8
Pages 2324-2335
Keywords Pathology and Forensic Medicine
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