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Inflammation and neutrophil extracellular traps in cerebral cavernous malformation

Cerebral Cavernous Malformation (CCM) is a brain vascular disease with various neurological symptoms. In this study, we describe the inflammatory profile in CCM and show for the first time the formation of neutrophil extracellular traps (NETs) in rodents and humans with CCM. Through RNA-seq analysis...

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Detalles Bibliográficos
Autores principales: Yau, Anthony C. Y., Globisch, Maria Ascencion, Onyeogaziri, Favour Chinyere, Conze, Lei L., Smith, Ross, Jauhiainen, Suvi, Corada, Monica, Orsenigo, Fabrizio, Huang, Hua, Herre, Melanie, Olsson, Anna-Karin, Malinverno, Matteo, Sundell, Veronica, Rezai Jahromi, Behnam, Niemelä, Mika, Laakso, Aki, Garlanda, Cecilia, Mantovani, Alberto, Lampugnani, Maria Grazia, Dejana, Elisabetta, Magnusson, Peetra U.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8949649/
https://www.ncbi.nlm.nih.gov/pubmed/35333979
http://dx.doi.org/10.1007/s00018-022-04224-2
Descripción
Sumario:Cerebral Cavernous Malformation (CCM) is a brain vascular disease with various neurological symptoms. In this study, we describe the inflammatory profile in CCM and show for the first time the formation of neutrophil extracellular traps (NETs) in rodents and humans with CCM. Through RNA-seq analysis of cerebellum endothelial cells from wild-type mice and mice with an endothelial cell-specific ablation of the Ccm3 gene (Ccm3(iECKO)), we show that endothelial cells from Ccm3(iECKO) mice have an increased expression of inflammation-related genes. These genes encode proinflammatory cytokines and chemokines, as well as adhesion molecules, which promote recruitment of inflammatory and immune cells. Similarly, immunoassays showed elevated levels of these cytokines and chemokines in the cerebellum of the Ccm3(iECKO) mice. Consistently, both flow cytometry and immunofluorescence analysis showed infiltration of different subsets of leukocytes into the CCM lesions. Neutrophils, which are known to fight against infection through different strategies, including the formation of NETs, represented the leukocyte subset within the most pronounced increase in CCM. Here, we detected elevated levels of NETs in the blood and the deposition of NETs in the cerebral cavernomas of Ccm3(iECKO) mice. Degradation of NETs by DNase I treatment improved the vascular barrier. The deposition of NETs in the cavernomas  of patients with CCM confirms the clinical relevance of NETs in CCM. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-022-04224-2.