Angiopoietin-like 4 protects against endothelial dysfunction during bacterial sepsis

Jason Ziveri; Loïc Le Guennec; Isabel dos Santos Souza; Jean Philipe Barnier; Samuel M. Walter; Youssouf Diallo; Yasmine Smail; Elodie Le Seac’h; Haniaa Bouzinba-Segard; Camille Faure; Philippe C. Morand; Irié Carel; Nicolas Perriere; Taliah Schmitt; Brigitte Izac; Franck Letourneur; Mathieu Coureuil; Thomas Rattei; Xavier Nassif; Sandrine Bourdoulous

doi:10.1038/s41564-024-01760-4

Angiopoietin-like 4 protects against endothelial dysfunction during bacterial sepsis

Jason Ziveri
, Loïc Le Guennec
, Isabel dos Santos Souza
, Jean Philipe Barnier
, Samuel M. Walter
, Youssouf Diallo
, Yasmine Smail
, Elodie Le Seac’h
, Haniaa Bouzinba-Segard
, Camille Faure
, Philippe C. Morand
, Irié Carel
, Nicolas Perriere
, Taliah Schmitt
, Brigitte Izac
, Franck Letourneur
, Mathieu Coureuil
, Thomas Rattei
, Xavier Nassif
, Sandrine Bourdoulous (Corresponding author)

Centre for Microbiology and Environmental Systems Science

Publications: Contribution to journal › Article › Peer Reviewed

Abstract

Loss of endothelial integrity and vascular leakage are central features of sepsis pathogenesis; however, no effective therapeutic mechanisms for preserving endothelial integrity are available. Here we show that, compared to dermal microvessels, brain microvessels resist infection by Neisseria meningitidis, a bacterial pathogen that causes sepsis and meningitis. By comparing the transcriptional responses to infection in dermal and brain endothelial cells, we identified angiopoietin-like 4 as a key factor produced by the brain endothelium that preserves blood–brain barrier integrity during bacterial sepsis. Conversely, angiopoietin-like 4 is produced at lower levels in the peripheral endothelium. Treatment with recombinant angiopoietin-like 4 reduced vascular leakage, organ failure and death in mouse models of lethal sepsis and N. meningitidis infection. Protection was conferred by a previously uncharacterized domain of angiopoietin-like 4, through binding to the heparan proteoglycan, syndecan-4. These findings reveal a potential strategy to prevent endothelial dysfunction and improve outcomes in patients with sepsis.

Original language	English
Pages (from-to)	2434-2447
Number of pages	14
Journal	Nature Microbiology
Volume	9
Issue number	9
DOIs	https://doi.org/10.1038/s41564-024-01760-4
Publication status	Published - 5 Aug 2024

Funding

The following funders provided support for this study: Agence Nationale de la Recherche ANR-14-IFEC14-0006 (S.B. and X.N.), Fondation pour la Recherche Médicale Equipe Grant EQU202003010400 (S.B.), Université Paris Cité IDEX UP 2020-S-I-001 (S.B.), Inserm transfert MAT-PI-19477-A-02 (S.B.), Austrian Science Fond FWF grant I 2191 (T.R.), Fondation pour la Recherche Médicale post-doctoral (J.Z.) and doctoral (L.L.G) fellowships and Université Paris Cité doctoral fellowship (I.d.S.S.). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

Austrian Fields of Science 2012

106022 Microbiology

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10.1038/s41564-024-01760-4

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Ziveri, J., Le Guennec, L., dos Santos Souza, I., Barnier, J. P., Walter, S. M., Diallo, Y., Smail, Y., Le Seac’h, E., Bouzinba-Segard, H., Faure, C., Morand, P. C., Carel, I., Perriere, N., Schmitt, T., Izac, B., Letourneur, F., Coureuil, M., Rattei, T., Nassif, X., & Bourdoulous, S. (2024). Angiopoietin-like 4 protects against endothelial dysfunction during bacterial sepsis. Nature Microbiology, 9(9), 2434-2447. https://doi.org/10.1038/s41564-024-01760-4

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abstract = "Loss of endothelial integrity and vascular leakage are central features of sepsis pathogenesis; however, no effective therapeutic mechanisms for preserving endothelial integrity are available. Here we show that, compared to dermal microvessels, brain microvessels resist infection by Neisseria meningitidis, a bacterial pathogen that causes sepsis and meningitis. By comparing the transcriptional responses to infection in dermal and brain endothelial cells, we identified angiopoietin-like 4 as a key factor produced by the brain endothelium that preserves blood–brain barrier integrity during bacterial sepsis. Conversely, angiopoietin-like 4 is produced at lower levels in the peripheral endothelium. Treatment with recombinant angiopoietin-like 4 reduced vascular leakage, organ failure and death in mouse models of lethal sepsis and N. meningitidis infection. Protection was conferred by a previously uncharacterized domain of angiopoietin-like 4, through binding to the heparan proteoglycan, syndecan-4. These findings reveal a potential strategy to prevent endothelial dysfunction and improve outcomes in patients with sepsis.",

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Ziveri, J, Le Guennec, L, dos Santos Souza, I, Barnier, JP, Walter, SM, Diallo, Y, Smail, Y, Le Seac’h, E, Bouzinba-Segard, H, Faure, C, Morand, PC, Carel, I, Perriere, N, Schmitt, T, Izac, B, Letourneur, F, Coureuil, M, Rattei, T, Nassif, X & Bourdoulous, S 2024, 'Angiopoietin-like 4 protects against endothelial dysfunction during bacterial sepsis', Nature Microbiology, vol. 9, no. 9, pp. 2434-2447. https://doi.org/10.1038/s41564-024-01760-4

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AU - Ziveri, Jason

AU - Le Guennec, Loïc

AU - dos Santos Souza, Isabel

AU - Barnier, Jean Philipe

AU - Walter, Samuel M.

AU - Diallo, Youssouf

AU - Smail, Yasmine

AU - Le Seac’h, Elodie

AU - Bouzinba-Segard, Haniaa

AU - Faure, Camille

AU - Morand, Philippe C.

AU - Carel, Irié

AU - Perriere, Nicolas

AU - Schmitt, Taliah

AU - Izac, Brigitte

AU - Letourneur, Franck

AU - Coureuil, Mathieu

AU - Rattei, Thomas

AU - Nassif, Xavier

AU - Bourdoulous, Sandrine

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N2 - Loss of endothelial integrity and vascular leakage are central features of sepsis pathogenesis; however, no effective therapeutic mechanisms for preserving endothelial integrity are available. Here we show that, compared to dermal microvessels, brain microvessels resist infection by Neisseria meningitidis, a bacterial pathogen that causes sepsis and meningitis. By comparing the transcriptional responses to infection in dermal and brain endothelial cells, we identified angiopoietin-like 4 as a key factor produced by the brain endothelium that preserves blood–brain barrier integrity during bacterial sepsis. Conversely, angiopoietin-like 4 is produced at lower levels in the peripheral endothelium. Treatment with recombinant angiopoietin-like 4 reduced vascular leakage, organ failure and death in mouse models of lethal sepsis and N. meningitidis infection. Protection was conferred by a previously uncharacterized domain of angiopoietin-like 4, through binding to the heparan proteoglycan, syndecan-4. These findings reveal a potential strategy to prevent endothelial dysfunction and improve outcomes in patients with sepsis.

AB - Loss of endothelial integrity and vascular leakage are central features of sepsis pathogenesis; however, no effective therapeutic mechanisms for preserving endothelial integrity are available. Here we show that, compared to dermal microvessels, brain microvessels resist infection by Neisseria meningitidis, a bacterial pathogen that causes sepsis and meningitis. By comparing the transcriptional responses to infection in dermal and brain endothelial cells, we identified angiopoietin-like 4 as a key factor produced by the brain endothelium that preserves blood–brain barrier integrity during bacterial sepsis. Conversely, angiopoietin-like 4 is produced at lower levels in the peripheral endothelium. Treatment with recombinant angiopoietin-like 4 reduced vascular leakage, organ failure and death in mouse models of lethal sepsis and N. meningitidis infection. Protection was conferred by a previously uncharacterized domain of angiopoietin-like 4, through binding to the heparan proteoglycan, syndecan-4. These findings reveal a potential strategy to prevent endothelial dysfunction and improve outcomes in patients with sepsis.

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EP - 2447

JO - Nature Microbiology

JF - Nature Microbiology

IS - 9

ER -

Angiopoietin-like 4 protects against endothelial dysfunction during bacterial sepsis

Abstract

Funding

Austrian Fields of Science 2012

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