Endothelial TLR4 and the microbiome drive cerebral cavernous malformations

Tang Alan T.; Hoi Jaesung P. C.; 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; Vosa 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.

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Endothelial TLR4 and the microbiome drive cerebral cavernous malformations

机译：内皮细胞TLR4和微生物组驱动脑海绵状畸形

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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.

机译：脑海绵状畸形（CCM）是中风和癫痫发作的原因，目前尚无有效的药物治疗方法。 CCMs是由衔接子复合物的丢失引起的，该衔接子复合物在脑内皮细胞中负调节MEKK3-KLF2 / 4信号传导，但该疾病途径的上游激活剂尚未确定。在这里，我们确定内皮Toll样受体4（TLR4）和肠道微生物组是CCM形成的关键刺激因素。革兰氏阴性菌或脂多糖对TLR4的激活会加速CCM的形成，而TLR4信号传导的遗传或药理学阻断作用可阻止小鼠中CCM的形成。增加TLR4基因或编码其共受体CD14的基因表达的多态性与人类较高的CCM病变负担相关。无病小鼠免受CCM形成的侵害，单疗程的抗生素会永久改变小鼠中CCM的敏感性。这些研究确定了微生物组和先天性免疫信号转导在脑血管疾病的发病机理中的意想不到的作用及其治疗策略。

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《Nature》 |2017年第7654期|305-310|共6页
作者
Tang Alan T.; Hoi Jaesung P. C.; 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; Vosa 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.;
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作者单位

Univ Penn, Dept Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA;

Centenary Inst, Lab Cardiovasc Signaling, Sydney, NSW 2050, Australia;

Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA;

Univ Penn, Dept Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA;

Univ Penn, Dept Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA;

Univ Chicago, Dept Surg, Sch Med & Biol Sci, Neurovasc Surg Program, 5841 S Maryland Ave, Chicago, IL 60637 USA;

Univ Chicago, Dept Surg, Sch Med & Biol Sci, Neurovasc Surg Program, 5841 S Maryland Ave, Chicago, IL 60637 USA;

Univ Chicago, Dept Surg, Sch Med & Biol Sci, Neurovasc Surg Program, 5841 S Maryland Ave, Chicago, IL 60637 USA;

Univ Chicago, Dept Surg, Sch Med & Biol Sci, Neurovasc Surg Program, 5841 S Maryland Ave, Chicago, IL 60637 USA;

Univ Chicago, Dept Surg, Sch Med & Biol Sci, Neurovasc Surg Program, 5841 S Maryland Ave, Chicago, IL 60637 USA;

Univ Chicago, Dept Surg, Sch Med & Biol Sci, Neurovasc Surg Program, 5841 S Maryland Ave, Chicago, IL 60637 USA;

Univ Chicago, Dept Surg, Sch Med & Biol Sci, Neurovasc Surg Program, 5841 S Maryland Ave, Chicago, IL 60637 USA;

Univ Penn, Dept Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA;

Univ Penn, Dept Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA;

Univ Penn, Dept Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA;

Univ Penn, Dept Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA;

Childrens Hosp Philadelphia, CHOP Microbiome Ctr, Philadelphia, PA 19104 USA;

Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA;

Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands;

Univ Utah, Div Cardiovasc Med, Salt Lake City, UT 84112 USA;

Univ Utah, Div Cardiovasc Med, Salt Lake City, UT 84112 USA;

Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands;

Univ New Mexico, Dept Neurol & Pediat, Albuquerque, NM 87131 USA;

Univ Lubeck, Inst Expt & Clin Pharmacol & Toxicol, D-23562 Lubeck, Germany;

Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA;

Univ New Mexico, Dept Neurol & Pediat, Albuquerque, NM 87131 USA;

Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, Ctr Cerebrovasc Res, San Francisco, CA 94143 USA;

Univ Chicago, Dept Surg, Sch Med & Biol Sci, Neurovasc Surg Program, 5841 S Maryland Ave, Chicago, IL 60637 USA;

Centenary Inst, Lab Cardiovasc Signaling, Sydney, NSW 2050, Australia;

Univ Penn, Dept Med, 3400 Civ Ctr Blvd, Philadelphia, PA 19104 USA;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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专利

1. Gut Microbiome and Endothelial TLR4 Activation Provoke Cerebral Cavernous Malformations [J] . Starke Robert M., McCarthy David J., Komotar Ricardo J., Clinical neurosurgery. . 2017,第5期

机译：肠道微生物组和内皮TLR4激活引起脑海绵状畸形
2. Gut Microbiome and Endothelial TLR4 Activation Provoke Cerebral Cavernous Malformations [J] . Starke Robert M., McCarthy David J., Komotar Ricardo J., Neurosurgery . 2017,第5期

机译：肠道微生物组和内皮TL4激活挑起脑海绵状畸形
3. Gut Microbiome and Endothelial TLR4 Activation Provoke Cerebral Cavernous Malformations [J] . Starke Robert M., McCarthy David J., Komotar Ricardo J., Neurosurgery . 2017,第5期

机译：肠道微生物组和内皮TL4激活挑起脑海绵状畸形
4. Automated detection of cavernous malformations in brain MRI images [C] . Huiquan Wang, S. Nizam Ahmed, Hongming Xu, International IEEE/EMBS Conference on Neural Engineering . 2017

机译：自动检测大脑MRI图像中的海绵状畸形
5. Defining the cerebral cavernous malformation protein signaling network in endothelial cells. [D] . Dibble, Christopher Francis. 2013

机译：在内皮细胞中定义脑海绵状畸形蛋白信号网络。
6. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations [O] . Alan T. Tang, Jaesung P. Choi, Jonathan J. Kotzin, -1

机译：内皮细胞TLR4和微生物组驱动脑海绵状畸形
7. Endothelial TLR4 and the microbiome drive cerebral cavernous malformations [O] . Tang, Alan T., Hoi, Jaesung P. C., Kotzin, Jonathan J., 2017

机译：内皮细胞TLR4和微生物组驱动脑海绵状畸形

Endothelial TLR4 and the microbiome drive cerebral cavernous malformations

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