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

作者：A. Tang, K. R. Sullivan, Courtney C Hong, Lauren M Goddard, Aparna Mahadevan, Aileen A. Ren, Heidy Pardo, Amy Peiper, Erin Griffin, C. Tanes, Lisa M. Mattei, Jisheng Yang, Li Li, Patricia Mericko-Ishizuka, Le Shen, N. Hobson, R. Girard, R. Lightle, Thomas Moore, R. Shenkar, S. Polster, C. Roedel, Ning Li, Qin Zhu, K. Whitehead, Xiangjian Zheng, Amy L. Akers, L. Morrison, Helen Kim, K. Bittinger, C. Lengner, M. Schwaninger, A. Velcich, L. Augenlicht, S. Abdelilah‐Seyfried, W. Min, D. Marchuk, I. Awad, M. Kahn · 发表于：Science Translational Medicine · 年份：2019 · DOI：10.1126/scitranslmed.aaw3521 · 被引用次数：66 · 研究领域：Biology、Medicine

Loss of PDCD10 signaling in brain endothelium and gut epithelium contribute to cerebral cavernous malformation in a mouse model. Two effects in one gene Cerebral cavernous malformation (CCM) is a genetic vascular disease affecting mainly the brain. Different genes can cause CCM and mutations in PDCD10 are responsible for a particularly severe form of the disease. Now, Tang et al. show that modulation of the gut barrier could explain the poor prognosis of patients with PDCD10 mutations. In mice, Pdcd10 deletion specifically in the gut epithelium disrupted the colonic mucosal barrier and increased CCM formation. Pharmacologic experiments targeting the glucocorticoid system demonstrated that both brain endothelial cells and gut epithelial cells contribute to CCM formation, suggesting that therapies targeting either brain or gut signaling could be effective for treating CCM. 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 demonstr...