Angiopoietin-like 4 protects against endothelial dysfunction during bacterial sepsis.
Nat Microbiol
; 9(9): 2434-2447, 2024 Sep.
Article
en En
| MEDLINE
| ID: mdl-39103571
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Sepsis
/
Células Endoteliales
/
Modelos Animales de Enfermedad
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Microbiol
Año:
2024
Tipo del documento:
Article
País de afiliación:
Francia