Endothelial TLR4 and the microbiome drive cerebral cavernous malformations.

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.

• Authors: Alan T Tang, Jaesung P Choi, Jonathan J Kotzin, Yiqing Yang, Courtney C Hong, Nicholas Hobson, Romuald Girard, Hussein A Zeineddine, Rhonda Lightle, Thomas Moore, Ying Cao, Robert Shenkar, Mei Chen, Patricia Mericko, Jisheng Yang, Li Li, Ceylan Tanes, Dmytro Kobuley, Urmo Võsa, Kevin J Whitehead, Dean Y Li, Lude Franke, Blaine Hart, Markus Schwaninger, Jorge Henao-Mejia, Leslie Morrison, Helen Kim, Issam A Awad, Xiangjian Zheng, Mark L Kahn
• Journal: Nature (Nature) Vol. 545 Issue 7654 Pg. 305-310 (05 18 2017) ISSN: 1476-4687 [Electronic] England
• PMID: 28489816 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Lipopolysaccharide Receptors
• Lipopolysaccharides
• TLR4 protein, human
• Toll-Like Receptor 4

Topics

• Animals
• Anti-Bacterial Agents (administration & dosage, pharmacology)
• Disease Susceptibility
• Endothelial Cells (metabolism)
• Female
• Gastrointestinal Microbiome (immunology)
• Germ-Free Life
• Gram-Negative Bacteria (immunology)
• Hemangioma, Cavernous, Central Nervous System (immunology, microbiology, pathology)
• Humans
• Immunity, Innate
• Injections, Intravenous
• Lipopolysaccharide Receptors (genetics, metabolism)
• Lipopolysaccharides (administration & dosage, immunology)
• Male
• Mice
• Signal Transduction
• Toll-Like Receptor 4 (antagonists & inhibitors, deficiency, genetics, immunology)