Endothelial TLR4 and the microbiome drive cerebral cavernous malformations.

Nature. 2017 May 18;545(7654):305-310. Epub 2017 May 10

Alan T Tang ¹ , Jaesung P Choi ² , Jonathan J Kotzin ³ , Yiqing Yang ¹ , Courtney C Hong ¹ ,

Alan T Tang ¹ , Jaesung P Choi ² , Jonathan J Kotzin ³ , Yiqing Yang ¹ , Courtney C Hong ¹ , Nicholas Hobson ⁴ , Romuald Girard ⁴ , Hussein A Zeineddine ⁴ , Rhonda Lightle ⁴ , Thomas Moore ⁴ , Ying Cao ⁴ , Robert Shenkar ⁴ , Mei Chen ¹ , Patricia Mericko ¹ , Jisheng Yang ¹ , Li Li ¹ , Ceylan Tanes ⁵ , Dmytro Kobuley ⁶ , Urmo Võsa ⁷ , Kevin J Whitehead ⁸ , Dean Y Li ⁸ , Lude Franke ⁷ , Blaine Hart ⁹ , Markus Schwaninger ¹⁰ , Jorge Henao-Mejia ¹¹ , Leslie Morrison ⁹ , Helen Kim ¹² , Issam A Awad ⁴ , Xiangjian Zheng ¹³ , Mark L Kahn ¹

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Author information

¹ Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.
² Laboratory of Cardiovascular Signaling, Centenary Institute, Sydney, New South Wales 2050, Australia.
³ Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
⁴ Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago School of Medicine and Biological Sciences, Chicago, Illinois 60637, USA.
⁵ CHOP Microbiome Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
⁶ Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
⁷ Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.
⁸ Division of Cardiovascular Medicine and the Program in Molecular Medicine, University of Utah, Salt Lake City, Utah 84112, USA.
⁹ Department of Neurology and Pediatrics, University of New Mexico, Albuquerque, New Mexico 87131, USA.
¹⁰ Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, 23562 Lübeck, Germany.
¹¹ Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
¹² Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California 94143, USA.
¹³ Department of Pharmacology, School of Basic Medical Sciences, Tianjian Medical University, Tianjin, China.

摘要

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.

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