Dataset Information

Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice: Implications for Superficial Erosion.

ABSTRACT:

Rationale

Superficial erosion currently causes up to a third of acute coronary syndromes; yet, we lack understanding of its mechanisms. Thrombi because of superficial intimal erosion characteristically complicate matrix-rich atheromata in regions of flow perturbation.

Objective

This study tested in vivo the involvement of disturbed flow and of neutrophils, hyaluronan, and Toll-like receptor 2 ligation in superficial intimal injury, a process implicated in superficial erosion.

Methods and results

In mouse carotid arteries with established intimal lesions tailored to resemble the substrate of human eroded plaques, acute flow perturbation promoted downstream endothelial cell activation, neutrophil accumulation, endothelial cell death and desquamation, and mural thrombosis. Neutrophil loss-of-function limited these findings. Toll-like receptor 2 agonism activated luminal endothelial cells, and deficiency of this innate immune receptor decreased intimal neutrophil adherence in regions of local flow disturbance, reducing endothelial cell injury and local thrombosis (P<0.05).

Conclusions

These results implicate flow disturbance, neutrophils, and Toll-like receptor 2 signaling as mechanisms that contribute to superficial erosion, a cause of acute coronary syndrome of likely growing importance in the statin era.

SUBMITTER: Franck G

PROVIDER: S-EPMC5488735 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Publications

Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice: Implications for Superficial Erosion.

Franck Grégory G Mawson Thomas T Sausen Grasiele G Salinas Manuel M Masson Gustavo Santos GS Cole Andrew A Beltrami-Moreira Marina M Chatzizisis Yiannis Y Quillard Thibault T Tesmenitsky Yevgenia Y Shvartz Eugenia E Sukhova Galina K GK Swirski Filip K FK Nahrendorf Matthias M Aikawa Elena E Croce Kevin J KJ Libby Peter P

Circulation research 20170420 1

<h4>Rationale</h4>Superficial erosion currently causes up to a third of acute coronary syndromes; yet, we lack understanding of its mechanisms. Thrombi because of superficial intimal erosion characteristically complicate matrix-rich atheromata in regions of flow perturbation.<h4>Objective</h4>This study tested in vivo the involvement of disturbed flow and of neutrophils, hyaluronan, and Toll-like receptor 2 ligation in superficial intimal injury, a process implicated in superficial erosion.<h4>M ...[more]

PMID: 28428204

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Project description:Excessive neutrophil extravasation can drive immunopathology, exemplified in pyogenic meningitis caused by Streptococcus pneumoniae infection. Insufficient knowledge of the mechanisms that amplify neutrophil extravasation has limited innovation in therapeutic targeting of neutrophil mediated pathology. Attention has focussed on neutrophil interactions with endothelia, but data from mouse models also point to a role for the underlying pericyte layer, as well as perivascular macrophages, the only other cell type found within the perivascular space in the cerebral microvasculature. We tested the hypothesis that human brain vascular pericytes (HBVP) contribute to neutrophil extravasation in a transwell model of the cerebral post-capillary venule. We show that pericytes augment endothelial barrier formation. In response to inflammatory cues, they significantly enhance neutrophil transmigration across the endothelial barrier, without increasing the permeability to small molecules. In our model, neither pericytes nor endothelia responded directly to bacterial stimulation. Instead, we show that paracrine signalling by multiple cytokines from monocyte derived macrophages drives transcriptional upregulation of multiple neutrophil chemokines by pericytes. Pericyte mediated amplification of neutrophil transmigration was independent of transcriptional responses by endothelia, but could be mediated by direct chemokine translocation across the endothelial barrier. Our data support a model in which microbial sensing by perivascular macrophages generates an inflammatory cascade where pericytes serve to amplify production of neutrophil chemokines that are translocated across the endothelial barrier to act directly on circulating neutrophils. In view of the striking redundancy in inflammatory cytokines that stimulate pericytes and in the neutrophil chemokines they produce, we propose that the mechanism of chemokine translocation may offer the most effective therapeutic target to reduce neutrophil mediated pathology in pyogenic meningitis.

Dataset Information

Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice: Implications for Superficial Erosion.

Rationale

Objective

Methods and results

Conclusions

Publications

Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice: Implications for Superficial Erosion.

Similar Datasets

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