Proinflammatory Stimulation of Toll-Like Receptor 9 with High Dose CpG ODN 1826 Impairs Endothelial Regeneration and Promotes Atherosclerosis in Mice
| Autor: | Georg Nickenig, Alexander O. Krogmann, Catharina Lahrmann, Tobias Asdonk, Martin Steinmetz, Sebastian Zimmer, Dieter Lütjohann, Enzo Lüsebrink |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
lcsh:Medicine 030204 cardiovascular system & hematology Mice 0302 clinical medicine Cell-Derived Microparticles immune system diseases Receptor lcsh:Science Aorta Cells Cultured Multidisciplinary hemic and immune systems Flow Cytometry Immunohistochemistry Carotid Arteries Oligodeoxyribonucleotides CpG site Cytokines medicine.symptom Research Article CpG Oligodeoxynucleotide DNA Single-Stranded Mice Transgenic chemical and pharmacologic phenomena Inflammation Biology Proinflammatory cytokine 03 medical and health sciences Apolipoproteins E parasitic diseases medicine Animals Humans Regeneration Vascular Diseases Innate immune system Body Weight lcsh:R TLR9 Atherosclerosis Toll-Like Receptor 9 Mice Inbred C57BL Disease Models Animal 030104 developmental biology Immunology Cancer research lcsh:Q Endothelium Vascular Reactive Oxygen Species Spleen |
| Zdroj: | PLoS ONE, Vol 11, Iss 1, p e0146326 (2016) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | BACKGROUND:Toll-like receptors (TLR) of the innate immune system have been closely linked with the development of atherosclerotic lesions. TLR9 is activated by unmethylated CpG motifs within ssDNA, but also by CpG motifs in nucleic acids released during vascular apoptosis and necrosis. The role of TLR9 in vascular disease remains controversial and we sought to investigate the effects of a proinflammatory TLR9 stimulation in mice. METHODS AND FINDINGS:TLR9-stimulation with high dose CpG ODN at concentrations between 6.25 nM to 30 nM induced a significant proinflammatory cytokine response in mice. This was associated with impaired reendothelialization upon acute denudation of the carotid and increased numbers of circulating endothelial microparticles, as a marker for amplified endothelial damage. Chronic TLR9 agonism in apolipoprotein E-deficient (ApoE-/-) mice fed a cholesterol-rich diet increased aortic production of reactive oxygen species, the number of circulating endothelial microparticles, circulating sca-1/flk-1 positive cells, and most importantly augmented atherosclerotic plaque formation when compared to vehicle treated animals. Importantly, high concentrations of CpG ODN are required for these proatherogenic effects. CONCLUSIONS:Systemic stimulation of TLR9 with high dose CpG ODN impaired reendothelialization upon acute vascular injury and increased atherosclerotic plaque development in ApoE-/- mice. Further studies are necessary to fully decipher the contradictory finding of TLR9 agonism in vascular biology. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|