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Sci Rep. 2016 Aug 25;6:31873. doi: 10.1038/srep31873.

Pleiotropic action of CpG-ODN on endothelium and macrophages attenuates angiogenesis through distinct pathways.

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Academic Unit of Ophthalmology, School of Clinical Sciences, University of Bristol, UK.
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Centre, Sun Yat-sen University, Guangzhou, China.
Centre for Clinic Immunology, Sun Yat-sen University Third Affiliated Hospital, Guangzhou, China.
UCL-Institute of Ophthalmology, University College London, London, UK.
Bristol Heart Institute, School of Clinical Sciences, University of Bristol, UK.
National Institute for Health Research (NIHR) Biomedical Research Centre, Moorfields Eye Hospital, London, UK.


There is an integral relationship between vascular cells and leukocytes in supporting healthy tissue homeostasis. Furthermore, activation of these two cellular components is key for tissue repair following injury. Toll-like receptors (TLRs) play a role in innate immunity defending the organism against infection, but their contribution to angiogenesis remains unclear. Here we used synthetic TLR9 agonists, cytosine-phosphate-guanosine oligodeoxynucleotides (CpG-ODN), to investigate the role of TLR9 in vascular pathophysiology and identify potential therapeutic translation. We demonstrate that CpG-ODN stimulates inflammation yet inhibits angiogenesis. Regulation of angiogenesis by CpG-ODN is pervasive and tissue non-specific. Further, we noted that synthetic CpG-ODN requires backbone phosphorothioate but not TLR9 activation to render and maintain endothelial stalk cells quiescent. CpG-ODN pre-treated endothelial cells enhance macrophage migration but restrain pericyte mobilisation. CpG-ODN attenuation of angiogenesis, however, remains TLR9-dependent, as inhibition is lost in TLR9 deficient mice. Additionally, CpG-ODNs induce an M1 macrophage phenotype that restricts angiogenesis. The effects mediated by CpG-ODNs can therefore modulate both endothelial cells and macrophages through distinct pathways, providing potential therapeutic application in ocular vascular disease.

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