Inflammation and neutrophil extracellular traps in cerebral cavernous malformation
Anthony C. Y. Yau, Maria Ascención Globisch, Favour Chinyere Onyeogaziri, Lei Liu Conze, Ross Smith, Suvi Jauhiainen, Monica Corada, Fabrizio Orsenigo, Hua Huang, Melanie Herre, Anna‐Karin Olsson, Matteo Malinverno, Veronica Sundell, Behnam Rezai Jahromi, Mika Niemelä, Aki Laakso, Cecília Garlanda, Alberto Mantovani, Maria Grazia Lampugnani, Elisabetta Dejana, Peetra U. Magnusson
Abstract
Abstract 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.