Viral mimetic triggers cerebral arteriopathy in juvenile brain via neutrophil elastase and NETosis

Rayasam, A. (author)

Jullienne, A. (author)

Chumak, Tetyana, 1982 (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology

Faustino, J. (author)

Szu, J. (author)

Hamer, M. (author)

Ek, C. Joakim (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology

Mallard, Carina, 1963 (author): Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi,Institute of Neuroscience and Physiology, Department of Physiology

Obenaus, A. (author)

Vexler, Z. S. (author)

(creator_code:org_t)

2021-07-22
2021
English.
In: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016.

Related links:: https://gup.ub.gu.se...; show more...; https://doi.org/10.1...; show less...

Abstract Subject headings

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 Polyinosinic:polycytidylic 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 (similar to 934Da) 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.

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)

By the author/editor: Rayasam, A.; Jullienne, A.; Chumak, Tetyana, ...; Faustino, J.; Szu, J.; Hamer, M.; show more...; Ek, C. Joakim; Mallard, Carina, ...; Obenaus, A.; Vexler, Z. S.; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Hematology

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

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