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

Stefan Roth, Vikramjeet Singh, Steffen Tiedt, Lisa Schindler, Georg Huber, Arie Geerlof, Daniel J Antoine, Antoine Anfray, Cyrille Orset, Maxime Gauberti, Antoine Fournier, Lesca M Holdt, Helena Erlandsson Harris, Britta Engelhardt, Marco E Bianchi, Denis Vivien, Christof Haffner, Jürgen Bernhagen, Martin Dichgans, Arthur Liesz

Research output: Contribution to journalArticlepeer-review

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 β3-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.

Original languageEnglish
JournalScience Translational Medicine
Volume10
Issue number432
DOIs
Publication statusPublished - 14 Mar 2018

Keywords

  • Journal Article

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