Research ArticleStroke

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

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Science Translational Medicine  14 Mar 2018:
Vol. 10, Issue 432, eaao1313
DOI: 10.1126/scitranslmed.aao1313

An alarmin(g) consequence of stroke

Patients surviving a stroke are at an increased risk for subsequent cardiovascular events. Preclinical models have shown accelerated atherosclerosis after stroke; however, the mechanisms underlying this enhanced plaque formation and inflammation in arteries have not been investigated. Now, Roth et al. have discovered that stroke-induced alarmin high-mobility group box 1 (HMGB1) release and sympathetic stress response activation exert a synergistic effect, resulting in exacerbation of atherosclerotic plaques in mice. The authors suggest that interfering with these processes after stroke might reduce the risk of secondary cardiovascular events.


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.

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