Brain-released alarmins and stress response synergize in accelerating atherosclerosis progression after stroke

S Roth, V Singh, S Tiedt, L Schindler, G Huber, A Geerlof, DJ Antoine, A Anfray, C Orset, M Gauberti, A Fournier, LM Holdt, HE Harris, B Engelhardt, ME Bianchi, D Vivien, C Haffner, J Bernhagen, M Dichgans, A Liesz

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Abstract

Stroke induces a multiphasic systemic immune response, but the consequences of this response on atherosclerosis-A major source of recurrent vascular events-have not been thoroughly investigated. We show that stroke exacerbates atheroprogression via alarmin-mediated propagation of vascular inflammation. The prototypic brain-released alarmin high-mobility group box 1 protein induced monocyte and endothelial activation via the receptor for advanced glycation end products (RAGE)-signaling cascade and increased plaque load and vulnerability. Recruitment of activated monocytes via the CC-chemokine ligand 2-CC-chemokine receptor type 2 pathway was critical in stroke-induced vascular inflammation. Neutralization of circulating alarmins or knockdown of RAGE attenuated atheroprogression. Blockage of ?3-Adrenoreceptors attenuated the egress of myeloid monocytes after stroke, whereas neutralization of circulating alarmins was required to reduce systemic monocyte activation and aortic invasion. Our findings identify a synergistic effect of the sympathetic stress response and alarmin-driven inflammation via RAGE as a critical mechanism of exacerbated atheroprogression after stroke. © 2018 The Authors, Some Rights Reserved.
Original languageEnglish
Article numbereaao1313
JournalScience Translational Medicine
Volume10
Issue number432
DOIs
Publication statusPublished - 2018

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    Roth, S., Singh, V., Tiedt, S., Schindler, L., Huber, G., Geerlof, A., Antoine, DJ., Anfray, A., Orset, C., Gauberti, M., Fournier, A., Holdt, LM., Harris, HE., Engelhardt, B., Bianchi, ME., Vivien, D., Haffner, C., Bernhagen, J., Dichgans, M., & Liesz, A. (2018). Brain-released alarmins and stress response synergize in accelerating atherosclerosis progression after stroke. Science Translational Medicine, 10(432), [eaao1313]. https://doi.org/10.1126/scitranslmed.aao1313