title: Pleiotropic action of CpG-ODN on endothelium and macrophages attenuates angiogenesis through distinct pathways.
abstract: 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.
authors: Academic Unit of Ophthalmology, School of Clinical Sciences, University of Bristol, UK.
authors: Jiahui
authors: J
authors: Wu
authors: 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.
authors: Wenru
authors: W
authors: Su
authors: UCL-Institute of Ophthalmology, University College London, London, UK.
authors: Michael B
authors: MB
authors: Powner
authors: Academic Unit of Ophthalmology, School of Clinical Sciences, University of Bristol, UK.
authors: Jian
authors: J
authors: Liu
authors: Academic Unit of Ophthalmology, School of Clinical Sciences, University of Bristol, UK.
authors: David A
authors: DA
authors: Copland
authors: UCL-Institute of Ophthalmology, University College London, London, UK.
authors: Marcus
authors: M
authors: Fruttiger
authors: Bristol Heart Institute, School of Clinical Sciences, University of Bristol, UK.
authors: Paolo
authors: P
authors: Madeddu
authors: Academic Unit of Ophthalmology, School of Clinical Sciences, University of Bristol, UK.|UCL-Institute of Ophthalmology, University College London, London, UK.|National Institute for Health Research (NIHR) Biomedical Research Centre, Moorfields Eye Hospital, London, UK.
authors: Andrew D
authors: AD
authors: Dick
authors: Academic Unit of Ophthalmology, School of Clinical Sciences, University of Bristol, UK.
authors: Lei
authors: L
authors: Liu
mesh_terms: D000818:Animals; D002465:Cell Movement; D016764:Cell Polarity / Q000187:drug effects; D002478:Cells, Cultured; D003315:Cornea / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004727:Endothelium / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000494:pharmacology; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
chemical_list: C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9