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Endothelial TLR4 and the microbiome drive cerebral cavernous malformations

Nature (London), 2017-05, Vol.545 (7654), p.305-310 [Peer Reviewed Journal]

COPYRIGHT 2017 Nature Publishing Group ;COPYRIGHT 2017 Nature Publishing Group ;Copyright Nature Publishing Group May 18, 2017 ;ISSN: 0028-0836 ;EISSN: 1476-4687 ;DOI: 10.1038/nature22075 ;PMID: 28489816

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Title:
Endothelial TLR4 and the microbiome drive cerebral cavernous malformations
Author: Tang, Alan T ; Choi, Jaesung P ; Kotzin, Jonathan J ; Yang, Yiqing ; Hong, Courtney C ; Hobson, Nicholas ; Girard, Romuald ; Zeineddine, Hussein A ; Lightle, Rhonda ; Moore, Thomas ; Cao, Ying ; Shenkar, Robert ; Chen, Mei ; Mericko, Patricia ; Yang, Jisheng ; Li, Li ; Tanes, Ceylan ; Kobuley, Dmytro ; Võsa, Urmo ; Whitehead, Kevin J ; Li, Dean Y ; Franke, Lude ; Hart, Blaine ; Schwaninger, Markus ; Henao-Mejia, Jorge ; Morrison, Leslie ; Kim, Helen ; Awad, Issam A ; Zheng, Xiangjian ; Kahn, Mark L
Subjects: Animals ; Anti-Bacterial Agents - administration & dosage ; Anti-Bacterial Agents - pharmacology ; Antibiotics ; Bacteria ; Brain ; Brain diseases ; Cavernous hemangioma ; CD14 antigen ; Disease Susceptibility ; Endothelial cells ; Endothelial Cells - metabolism ; Female ; Gastrointestinal Microbiome - immunology ; Gene expression ; Germ-Free Life ; Germfree ; Gram-negative bacteria ; Gram-Negative Bacteria - immunology ; Health aspects ; Hemangioma, Cavernous ; Hemangioma, Cavernous, Central Nervous System - immunology ; Hemangioma, Cavernous, Central Nervous System - microbiology ; Hemangioma, Cavernous, Central Nervous System - pathology ; Humans ; Immune system ; Immunity, Innate ; Injections, Intravenous ; Intestinal microflora ; Lipopolysaccharide Receptors - genetics ; Lipopolysaccharide Receptors - metabolism ; Lipopolysaccharides ; Lipopolysaccharides - administration & dosage ; Lipopolysaccharides - immunology ; Lung Kruppel-like factor ; Male ; Mice ; Pathogenesis ; Pharmacology ; Physiological aspects ; Proteins ; Signal Transduction ; Signaling ; Stimulants ; Stroke ; TLR4 protein ; Toll-Like Receptor 4 - antagonists & inhibitors ; Toll-Like Receptor 4 - deficiency ; Toll-Like Receptor 4 - genetics ; Toll-Like Receptor 4 - immunology ; Toll-like receptors
Is Part Of: Nature (London), 2017-05, Vol.545 (7654), p.305-310
Description: Cerebral cavernous malformations (CCMs) are a cause of stroke and seizure for which no effective medical therapies yet exist. CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3-KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified. Here we identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of CCM formation. Activation of TLR4 by Gram-negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment.
Publisher: England: Nature Publishing Group
Language: English
Identifier: ISSN: 0028-0836
EISSN: 1476-4687
DOI: 10.1038/nature22075
PMID: 28489816
Source: ProQuest One Psychology
MEDLINE
ProQuest Central

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Endothelial TLR4 and the microbiome drive cerebral cavernous malformations

COPYRIGHT 2017 Nature Publishing Group ;COPYRIGHT 2017 Nature Publishing Group ;Copyright Nature Publishing Group May 18, 2017 ;ISSN: 0028-0836 ;EISSN: 1476-4687 ;DOI: 10.1038/nature22075 ;PMID: 28489816

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