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.

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.

Citation

Wu, W.-K., Georgiadis, A., Copland, D. A., Liyanage, S., Luhmann, U. F., Robbie, S. J., Liu, J., Wu, J., Bainbridge, J. W., Bates, D. O., Ali, R. R., Nicholson, L. B., & Dick, A. D. (2015). IL-4 Regulates Specific Arg-1+ Macrophage sFlt-1–Mediated Inhibition of Angiogenesis. American Journal of Pathology, 185(8), 2324-2335. https://doi.org/10.1016/j.ajpath.2015.04.013

• 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
• DOI: https://doi.org/10.1016/j.ajpath.2015.04.013
• Keywords: Pathology and Forensic Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/1478582
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0002944015002710?via%3Dihub