Molecular Signaling and Dysfunction of the Human Reactive Enteric Glial Cell Phenotype

作者：Andrómeda Liñán-Rico, Fabio Turco, Fernando Ochoa‐Cortés, Alan Harzman, Bradley Needleman, Razvan Arsenescu, Mahmoud Abdel‐Rasoul, Paolo Fadda, Iveta Grants, Emmett E. Whitaker, Rosario Cuomo, Fievos L. Christofi · 发表于：Inflammatory Bowel Diseases · 年份：2016 · DOI：10.1097/mib.0000000000000854 · 被引用次数：107 · 研究领域：Gastrointestinal motility and disorders、Congenital gastrointestinal and neural anomalies、Barrier Structure and Function Studies

BACKGROUND: Clinical observations or animal studies implicate enteric glial cells in motility disorders, irritable bowel syndrome, inflammatory bowel disease, gastrointestinal (GI) infections, postoperative ileus, and slow transit constipation. Mechanisms underlying glial responses to inflammation in human GI tract are not understood. Our goal was to identify the "reactive human enteric glial cell (rhEGC) phenotype" induced by inflammation, and probe its functional relevance. METHODS: Human enteric glial cells in culture from 15 GI-surgical specimens were used to study gene expression, Ca, and purinergic signaling by Ca/fluo-4 imaging and mechanosensitivity. A nanostring panel of 107 genes was designed as a read out of inflammation, transcription, purinergic signaling, vesicular transport protein, channel, antioxidant, and other pathways. A 24-hour treatment with lipopolysaccharide (200 μg/mL) and interferon-γ (10 μg/mL) was used to induce inflammation and study molecular signaling, flow-dependent Ca responses from 3 mL/min to 10 mL/min, adenosine triphosphate (ATP) release, and ATP responses. RESULTS: Treatment induced a "rhEGC phenotype" and caused up-regulation in messenger RNA transcripts of 58% of 107 genes analyzed. Regulated genes included inflammatory genes (54%/IP10; IFN-γ; CxCl2; CCL3; CCL2; C3; s100B; IL-1β; IL-2R; TNF-α; IL-4; IL-6; IL-8; IL-10; IL-12A; IL-17A; IL-22; and IL-33), purine-genes (52%/AdoR2A; AdoR2B; P2RY1; P2RY2; P2RY6; P2RX3; P2RX7; AMPD3; ENTPD2; E...