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: Wei-Kang Wu, Anastasios Georgiadis, David A Copland, Sidath Liyanage, Ulrich F O Luhmann, Scott J Robbie, Jian Liu, Jiahui Wu, James W Bainbridge, David O Bates, Robin R Ali, Lindsay B Nicholson, Andrew D Dick
• Journal: The American journal of pathology (Am J Pathol) Vol. 185 Issue 8 Pg. 2324-35 (Aug 2015) ISSN: 1525-2191 [Electronic] United States
• PMID: 26079814 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Interleukin-13
• Vascular Endothelial Growth Factor A
• Interleukin-4
• FLT1 protein, human
• Vascular Endothelial Growth Factor Receptor-1
• ARG1 protein, human
• Arginase

Topics

• Animals
• Arginase (metabolism)
• Cell Proliferation (drug effects)
• Choroidal Neovascularization (metabolism)
• Disease Models, Animal
• Humans
• Interleukin-13 (pharmacology)
• Interleukin-4 (pharmacology)
• Macrophages (drug effects, metabolism)
• Mice
• Retina (drug effects, metabolism)
• Retinal Pigment Epithelium (metabolism)
• Vascular Endothelial Growth Factor A (metabolism)
• Vascular Endothelial Growth Factor Receptor-1 (metabolism)