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Pericyte derived chemokines amplify neutrophil recruitment across the cerebrovascular endothelial barrier

Gil, Eliza; Venturini, Cristina; Stirling, David; Turner, Carolin; Tezera, Liku B; Ercoli, Giuseppe; Baker, Tina; ... Noursadeghi, Mahdad; + view all (2022) Pericyte derived chemokines amplify neutrophil recruitment across the cerebrovascular endothelial barrier. Frontiers in Immunology , 13 , Article 935798. 10.3389/fimmu.2022.935798. Green open access

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Abstract

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.

Type: Article
Title: Pericyte derived chemokines amplify neutrophil recruitment across the cerebrovascular endothelial barrier
Location: Switzerland
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fimmu.2022.935798
Publisher version: https://doi.org/10.3389/fimmu.2022.935798
Language: English
Additional information: Copyright © 2022 Gil, Venturini, Stirling, Turner, Tezera, Ercoli, Baker, Best, Brown and Noursadeghi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: Streptococcus pneumoniae, blood-brain barrier, macrophages, meningitis, neutrophils, pericytes
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10153991
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