Pericyte derived chemokines amplify neutrophil recruitment across the cerebrovascular endothelial barrier
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 patholo...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.935798/full |
| _version_ | 1818002111676284928 |
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| author | Eliza Gil Cristina Venturini David Stirling Carolin Turner Liku B. Tezera Liku B. Tezera Giuseppe Ercoli Tina Baker Katharine Best Jeremy S. Brown Mahdad Noursadeghi |
| author_facet | Eliza Gil Cristina Venturini David Stirling Carolin Turner Liku B. Tezera Liku B. Tezera Giuseppe Ercoli Tina Baker Katharine Best Jeremy S. Brown Mahdad Noursadeghi |
| author_sort | Eliza Gil |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-14T03:42:31Z |
| format | Article |
| id | doaj.art-a1022fcbd695495aa8d565e564c8c482 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-14T03:42:31Z |
| publishDate | 2022-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-a1022fcbd695495aa8d565e564c8c4822022-12-22T02:14:29ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-07-011310.3389/fimmu.2022.935798935798Pericyte derived chemokines amplify neutrophil recruitment across the cerebrovascular endothelial barrierEliza Gil0Cristina Venturini1David Stirling2Carolin Turner3Liku B. Tezera4Liku B. Tezera5Giuseppe Ercoli6Tina Baker7Katharine Best8Jeremy S. Brown9Mahdad Noursadeghi10Division of Infection and Immunity, University College London, London, United KingdomInfection, Immunity and Inflammation Department, Institute for Child Health, University College London, London, United KingdomDivision of Infection and Immunity, University College London, London, United KingdomDivision of Infection and Immunity, University College London, London, United KingdomDivision of Infection and Immunity, University College London, London, United KingdomNIHR Biomedical Research Center, School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United KingdomCentre for Inflammation and Tissue Repair, Division of Medicine, University College London, London, United KingdomDivision of Infection and Immunity, University College London, London, United KingdomDivision of Infection and Immunity, University College London, London, United KingdomCentre for Inflammation and Tissue Repair, Division of Medicine, University College London, London, United KingdomDivision of Infection and Immunity, University College London, London, United KingdomExcessive 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.https://www.frontiersin.org/articles/10.3389/fimmu.2022.935798/fullmeningitisblood-brain barrierneutrophilspericytesmacrophagesStreptococcus pneumoniae |
| spellingShingle | Eliza Gil Cristina Venturini David Stirling Carolin Turner Liku B. Tezera Liku B. Tezera Giuseppe Ercoli Tina Baker Katharine Best Jeremy S. Brown Mahdad Noursadeghi Pericyte derived chemokines amplify neutrophil recruitment across the cerebrovascular endothelial barrier Frontiers in Immunology meningitis blood-brain barrier neutrophils pericytes macrophages Streptococcus pneumoniae |
| title | Pericyte derived chemokines amplify neutrophil recruitment across the cerebrovascular endothelial barrier |
| title_full | Pericyte derived chemokines amplify neutrophil recruitment across the cerebrovascular endothelial barrier |
| title_fullStr | Pericyte derived chemokines amplify neutrophil recruitment across the cerebrovascular endothelial barrier |
| title_full_unstemmed | Pericyte derived chemokines amplify neutrophil recruitment across the cerebrovascular endothelial barrier |
| title_short | Pericyte derived chemokines amplify neutrophil recruitment across the cerebrovascular endothelial barrier |
| title_sort | pericyte derived chemokines amplify neutrophil recruitment across the cerebrovascular endothelial barrier |
| topic | meningitis blood-brain barrier neutrophils pericytes macrophages Streptococcus pneumoniae |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.935798/full |
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