Viral mimetic triggers cerebral arteriopathy in juvenile brain via neutrophil elastase and NETosis.
J Cereb Blood Flow Metab
; 41(12): 3171-3186, 2021 12.
Article
en En
| MEDLINE
| ID: mdl-34293939
ABSTRACT
Stroke is among the top ten causes of death in children but has received disproportionally little attention. Cerebral arteriopathies account for up to 80% of childhood arterial ischemic stroke (CAIS) cases and are strongly predictive of CAIS recurrence and poorer outcomes. The underlying mechanisms of sensitization of neurovasculature by viral infection are undefined. In the first age-appropriate model for childhood arteriopathy-by administration of viral mimetic TLR3-agonist Polyinosinicpolycytidylic acid (Poly-IC) in juvenile mice-we identified a key role of the TLR3-neutrophil axis in disrupting the structural-functional integrity of the blood-brain barrier (BBB) and distorting the developing neurovascular architecture and vascular networks. First, using an array of in-vivo/post-vivo vascular imaging, genetic, enzymatic and pharmacological approaches, we report marked Poly-IC-mediated extravascular leakage of albumin (66kDa) and of a small molecule DiI (â¼934Da) and disrupted tight junctions. Poly-IC also enhanced the neuroinflammatory milieu, promoted neutrophil recruitment, profoundly upregulated neutrophil elastase (NE), and induced neutrophil extracellular trap formation (NETosis). Finally, we show that functional BBB disturbances, NETosis and neuroinflammation are markedly attenuated by pharmacological inhibition of NE (Sivelestat). Altogether, these data reveal NE/NETosis as a novel therapeutic target for viral-induced cerebral arteriopathies in children.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Arterias Cerebrales
/
Poli I-C
/
Elastasa de Leucocito
/
Accidente Cerebrovascular
/
Trampas Extracelulares
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Child
/
Humans
Idioma:
En
Revista:
J Cereb Blood Flow Metab
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos