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

Alan T. Tang, Katie R. Sullivan, Courtney C. Hong, Lauren M. Goddard, Aparna Mahadevan, Aileen Ren, Heidy Pardo, Amy Peiper, Erin Griffin, Ceylan Tanes, Lisa M. Mattei, Jisheng Yang, Li Li, Patricia Mericko-Ishizuka, Le Shen, Nicholas Hobson, Romuald Girard, Rhonda Lightle, Thomas Moore, Robert ShenkarSean P. Polster, Claudia J. Roedel, Ning Li, Qin Zhu, Kevin J. Whitehead, Xiangjian Zheng, Amy Akers, Leslie Morrison, Helen Kim, Kyle Bittinger, Christopher J. Lengner, Markus Schwaninger, Anna Velcich, Leonard Augenlicht, Salim Abdelilah-Seyfried, Wang Min, Douglas A. Marchuk, Issam A. Awad, Mark L. Kahn

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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.

Original languageEnglish (US)
Article numbereaaw3521
JournalScience translational medicine
Volume11
Issue number520
DOIs
StatePublished - Nov 27 2019

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ASJC Scopus subject areas

  • Medicine(all)

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Tang, A. T., Sullivan, K. R., Hong, C. C., Goddard, L. M., Mahadevan, A., Ren, A., Pardo, H., Peiper, A., Griffin, E., Tanes, C., Mattei, L. M., Yang, J., Li, L., Mericko-Ishizuka, P., Shen, L., Hobson, N., Girard, R., Lightle, R., Moore, T., ... Kahn, M. L. (2019). Distinct cellular roles for PDCD10 define a gut-brain axis in cerebral cavernous malformation. Science translational medicine, 11(520), [eaaw3521]. https://doi.org/10.1126/scitranslmed.aaw3521