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Sci Transl Med. 2019 Nov 27;11(520). pii: eaaw3521. doi: 10.1126/scitranslmed.aaw3521.

Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation.

Author information

1
Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA.
2
Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA.
3
Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
4
Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, University of Chicago School of Medicine and Biological Sciences, Chicago, IL 60637, USA.
5
Institute for Biochemistry and Biology, Department of Animal Physiology, Potsdam University, Karl-Liebknecht-Str. 24-25, Haus 26, 14476 Potsdam, Germany.
6
Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
7
Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
8
Division of Cardiovascular Medicine and the Program in Molecular Medicine, University of Utah, Salt Lake City, UT 84112, USA.
9
Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
10
Centenary Institute, Sydney Medical School, University of Sydney, Sydney, NSW 2050, Australia.
11
Angioma Alliance, Norfolk, VA 23517, USA.
12
Department of Neurology and Pediatrics, University of New Mexico, Albuquerque, NM 87106, USA.
13
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA 94110, USA.
14
Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
15
Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
16
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, 23562 Lübeck, Germany.
17
Department of Cell Biology, Albert Einstein College of Medicine/Albert Einstein Cancer Center, NY 10461, USA.
18
Institute of Molecular Biology, Hannover Medical School, Carl-Neuberg Str. 1, D-30625 Hannover, Germany.
19
Department of Pathology and the Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06510, USA.
20
Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, USA. markkahn@pennmedicine.upenn.edu.

Abstract

Cerebral cavernous malformation (CCM) is a genetic, cerebrovascular disease. Familial CCM is caused by genetic mutations in KRIT1, CCM2, or PDCD10 Disease onset is earlier and more severe in individuals with PDCD10 mutations. Recent studies have shown that lesions arise from excess mitogen-activated protein kinase kinase kinase 3 (MEKK3) signaling downstream of Toll-like receptor 4 (TLR4) stimulation by lipopolysaccharide derived from the gut microbiome. These findings suggest a gut-brain CCM disease axis but fail to define it or explain the poor prognosis of patients with PDCD10 mutations. Here, we demonstrate that the gut barrier is a primary determinant of CCM disease course, independent of microbiome configuration, that explains the increased severity of CCM disease associated with PDCD10 deficiency. Chemical disruption of the gut barrier with dextran sulfate sodium augments CCM formation in a mouse model, as does genetic loss of Pdcd10, but not Krit1, in gut epithelial cells. Loss of gut epithelial Pdcd10 results in disruption of the colonic mucosal barrier. Accordingly, loss of Mucin-2 or exposure to dietary emulsifiers that reduce the mucus barrier increases CCM burden analogous to loss of Pdcd10 in the gut epithelium. Last, we show that treatment with dexamethasone potently inhibits CCM formation in mice because of the combined effect of action at both brain endothelial cells and gut epithelial cells. These studies define a gut-brain disease axis in an experimental model of CCM in which a single gene is required for two critical components: gut epithelial function and brain endothelial signaling.

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