Endothelial TLR4 and the microbiome drive cerebral cavernous malformations.

Tang, AT; Choi, JP; Kotzin, JJ; Yang, Y; Hong, CC; Hobson, N; Girard, R; Zeineddine, HA; Lightle, R; Moore, T; Cao, Y; Shenkar, R; Chen, M; Mericko, P; Yang, J; Li, L; Tanes, C; Kobuley, D; Võsa, U; Whitehead, KJ; Li, DY; Franke, L; Hart, B; Schwaninger, M; Henao-Mejia, J; Morrison, L; Kim, H; Awad, IA; Zheng, X; Kahn, ML

Endothelial TLR4 and the microbiome drive cerebral cavernous malformations.

Tang, AT Choi, JP Kotzin, JJ Yang, Y Hong, CC Hobson, N Girard, R Zeineddine, HA Lightle, R Moore, T Cao, Y Shenkar, R Chen, M Mericko, P Yang, J Li, L Tanes, C Kobuley, D Võsa, U Whitehead, KJ Li, DY Franke, L Hart, B Schwaninger, M Henao-Mejia, J Morrison, L Kim, H Awad, IA Zheng, X Kahn, ML

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Publisher:: Nature Research
Publication Type:: Journal Article
Citation:: Nature, 2017, 545, (7654), pp. 305-310
Issue Date:: 2017-05-18

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Field	Value	Language
dc.contributor.author	Tang, AT
dc.contributor.author	Choi, JP
dc.contributor.author	Kotzin, JJ
dc.contributor.author	Yang, Y
dc.contributor.author	Hong, CC
dc.contributor.author	Hobson, N
dc.contributor.author	Girard, R
dc.contributor.author	Zeineddine, HA
dc.contributor.author	Lightle, R
dc.contributor.author	Moore, T
dc.contributor.author	Cao, Y
dc.contributor.author	Shenkar, R
dc.contributor.author	Chen, M
dc.contributor.author	Mericko, P
dc.contributor.author	Yang, J
dc.contributor.author	Li, L
dc.contributor.author	Tanes, C
dc.contributor.author	Kobuley, D
dc.contributor.author	Võsa, U
dc.contributor.author	Whitehead, KJ
dc.contributor.author	Li, DY
dc.contributor.author	Franke, L
dc.contributor.author	Hart, B
dc.contributor.author	Schwaninger, M
dc.contributor.author	Henao-Mejia, J
dc.contributor.author	Morrison, L
dc.contributor.author	Kim, H
dc.contributor.author	Awad, IA
dc.contributor.author	Zheng, X
dc.contributor.author	Kahn, ML
dc.date.accessioned	2022-08-30T04:49:50Z
dc.date.available	2017-03-20
dc.date.available	2022-08-30T04:49:50Z
dc.date.issued	2017-05-18
dc.identifier.citation	Nature, 2017, 545, (7654), pp. 305-310
dc.identifier.issn	0028-0836
dc.identifier.issn	1476-4687
dc.identifier.uri	http://hdl.handle.net/10453/161112
dc.description.abstract	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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Nature Research
dc.relation.ispartof	Nature
dc.relation.isbasedon	10.1038/nature22075
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject.classification	General Science & Technology
dc.subject.mesh	Animals
dc.subject.mesh	Anti-Bacterial Agents
dc.subject.mesh	Disease Susceptibility
dc.subject.mesh	Endothelial Cells
dc.subject.mesh	Female
dc.subject.mesh	Gastrointestinal Microbiome
dc.subject.mesh	Germ-Free Life
dc.subject.mesh	Gram-Negative Bacteria
dc.subject.mesh	Hemangioma, Cavernous, Central Nervous System
dc.subject.mesh	Humans
dc.subject.mesh	Immunity, Innate
dc.subject.mesh	Injections, Intravenous
dc.subject.mesh	Lipopolysaccharide Receptors
dc.subject.mesh	Lipopolysaccharides
dc.subject.mesh	Male
dc.subject.mesh	Mice
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Toll-Like Receptor 4
dc.subject.mesh	Animals
dc.subject.mesh	Anti-Bacterial Agents
dc.subject.mesh	Disease Susceptibility
dc.subject.mesh	Endothelial Cells
dc.subject.mesh	Female
dc.subject.mesh	Gastrointestinal Microbiome
dc.subject.mesh	Germ-Free Life
dc.subject.mesh	Gram-Negative Bacteria
dc.subject.mesh	Hemangioma, Cavernous, Central Nervous System
dc.subject.mesh	Humans
dc.subject.mesh	Immunity, Innate
dc.subject.mesh	Injections, Intravenous
dc.subject.mesh	Lipopolysaccharide Receptors
dc.subject.mesh	Lipopolysaccharides
dc.subject.mesh	Male
dc.subject.mesh	Mice
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Toll-Like Receptor 4
dc.subject.mesh	Endothelial Cells
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Gram-Negative Bacteria
dc.subject.mesh	Hemangioma, Cavernous, Central Nervous System
dc.subject.mesh	Disease Susceptibility
dc.subject.mesh	Lipopolysaccharides
dc.subject.mesh	Anti-Bacterial Agents
dc.subject.mesh	Injections, Intravenous
dc.subject.mesh	Germ-Free Life
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Toll-Like Receptor 4
dc.subject.mesh	Immunity, Innate
dc.subject.mesh	Gastrointestinal Microbiome
dc.subject.mesh	Lipopolysaccharide Receptors
dc.title	Endothelial TLR4 and the microbiome drive cerebral cavernous malformations.
dc.type	Journal Article
utslib.citation.volume	545
utslib.location.activity	England
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	closed_access	*
pubs.consider-herdc	false
dc.date.updated	2022-08-30T04:49:37Z
pubs.issue	7654
pubs.publication-status	Published
pubs.volume	545
utslib.citation.issue	7654

Abstract:

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/161112