Endothelial TLR4 and the microbiome drive cerebral cavernous malformations

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 and Mark L. Kahn ()
Additional contact information
Alan T. Tang: University of Pennsylvania, 3400 Civic Center Boulevard
Jaesung P. Choi: Laboratory of Cardiovascular Signaling, Centenary Institute
Jonathan J. Kotzin: University of Pennsylvania
Yiqing Yang: University of Pennsylvania, 3400 Civic Center Boulevard
Courtney C. Hong: University of Pennsylvania, 3400 Civic Center Boulevard
Nicholas Hobson: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago School of Medicine and Biological Sciences
Romuald Girard: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago School of Medicine and Biological Sciences
Hussein A. Zeineddine: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago School of Medicine and Biological Sciences
Rhonda Lightle: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago School of Medicine and Biological Sciences
Thomas Moore: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago School of Medicine and Biological Sciences
Ying Cao: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago School of Medicine and Biological Sciences
Robert Shenkar: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago School of Medicine and Biological Sciences
Mei Chen: University of Pennsylvania, 3400 Civic Center Boulevard
Patricia Mericko: University of Pennsylvania, 3400 Civic Center Boulevard
Jisheng Yang: University of Pennsylvania, 3400 Civic Center Boulevard
Li Li: University of Pennsylvania, 3400 Civic Center Boulevard
Ceylan Tanes: CHOP Microbiome Center, The Children’s Hospital of Philadelphia
Dmytro Kobuley: Institute for Immunology, Perelman School of Medicine, University of Pennsylvania
Urmo Võsa: University Medical Centre Groningen, University of Groningen
Kevin J. Whitehead: University of Utah
Dean Y. Li: University of Utah
Lude Franke: University Medical Centre Groningen, University of Groningen
Blaine Hart: University of New Mexico
Markus Schwaninger: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck
Jorge Henao-Mejia: University of Pennsylvania
Leslie Morrison: University of New Mexico
Helen Kim: Center for Cerebrovascular Research, University of California San Francisco
Issam A. Awad: Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago School of Medicine and Biological Sciences
Xiangjian Zheng: Laboratory of Cardiovascular Signaling, Centenary Institute
Mark L. Kahn: University of Pennsylvania, 3400 Civic Center Boulevard

Nature, 2017, vol. 545, issue 7654, 305-310

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature22075

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