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Apoptotic Cell Clearance in Health and Disease

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Front. Immunol. | doi: 10.3389/fimmu.2018.00768

Soluble mediators produced by pro-resolving macrophages inhibit angiogenesis.

Shira Michaeli1, Vivian Dakwar1, Keren Weidenfeld1, Ortal Granski1, Sagie Shif1, Anatolii Mamchur2, Imad Shams2 and  Dalit Barkan1*
  • 1Department of Human Bioogy, University of Haifa, Israel
  • 2Department of Evolutionary and Environmental Biology, University of Haifa, Israel

Different subtypes of macrophages have been shown to participate during the different stages in tissue repair. In the late stage of tissue repair the macrophages, following their engulfment of apoptotic neutrophils, acquire a new phenotype termed alternatively-activated macrophages. These macrophages produce growth factors such as vascular endothelial growth factor (VEGF) that facilitate angiogenic response as part of tissue restoration. As the wound resolves capillary regression takes place. However, whether macrophages play a role in this late stage of tissue repair is largely unknown. Here, we examined whether soluble mediators secreted by pro-resolving CD11blow macrophages (Mres) will inhibit angiogenesis as part of the resolution of tissue repair. Our findings indicate that soluble mediators produced by ex-vivo generated Mres attenuate angiogenesis in vitro by inhibiting human umbilical endothelial cell (HUVEC) proliferation by lowering cyclin D1 expression, their survival by inducing caspase 3/7 activation and by inhibiting VEGFR2 activation via VEGF. In addition, soluble mediators secreted by Mres inhibit HUVEC migration and differentiation to tubular-like structure. Similarly, bioactive mediators produced by Mres significantly inhibit neovascularization as depicted ex vivo by utilizing the rat aorta ring assay and in vivo by utilizing the chick chorioallantoic membrane (CAM) assay. Notably, endostatin which was shown previously to exert its anti-angiogenic effect by inhibiting proliferation, survival, motility and morphogenesis of endothelial cells via inhibition of VEGFR2 activation, is produced by Mres. Taken together our results suggest that a specialized subset of macrophages that appear during the resolution of inflammation can produce anti-angiogenic mediators, such as endostatin. These mediators can resolve angiogenesis, thus ensuring tissue restoration to its homeostatic state.

Keywords: Pro-resolving macrophages, anti-angiogenic factors, endostatin, resolution of inflammation., tissue repair

Received: 06 Nov 2017; Accepted: 27 Mar 2018.

Edited by:

Estee Kurant, University of Haifa, Israel

Reviewed by:

Michal A. Rahat, Technion – Israel Institute of Technology, Israel
Hynda K. Kleinman, School of Medicine and Health Sciences, George Washington University, United States  

Copyright: © 2018 Michaeli, Dakwar, Weidenfeld, Granski, Shif, Mamchur, Shams and Barkan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Dalit Barkan, University of Haifa, Department of Human Bioogy, Haifa, Israel,