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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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
Issue number432
Publication statusPublished - 2018


Cite this

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].