@article{d4f6b402b77040949d26ba08aee3873f,
title = "A novel P2X2-dependent purinergic mechanism of enteric gliosis in intestinal inflammation",
abstract = "Enteric glial cells (EGC) modulate motility, maintain gut homeostasis, and contribute to neuroinflammation in intestinal diseases and motility disorders. Damage induces a reactive glial phenotype known as “gliosis”, but the molecular identity of the inducing mechanism and triggers of “enteric gliosis” are poorly understood. We tested the hypothesis that surgical trauma during intestinal surgery triggers ATP release that drives enteric gliosis and inflammation leading to impaired motility in postoperative ileus (POI). ATP activation of a p38-dependent MAPK pathway triggers cytokine release and a gliosis phenotype in murine (and human) EGCs. Receptor antagonism and genetic depletion studies revealed P2X2 as the relevant ATP receptor and pharmacological screenings identified ambroxol as a novel P2X2 antagonist. Ambroxol prevented ATP-induced enteric gliosis, inflammation, and protected against dysmotility, while abrogating enteric gliosis in human intestine exposed to surgical trauma. We identified a novel pathogenic P2X2-dependent pathway of ATP-induced enteric gliosis, inflammation and dysmotility in humans and mice. Interventions that block enteric glial P2X2 receptors during trauma may represent a novel therapy in treating POI and immune-driven intestinal motility disorders.",
keywords = "enteric nervous system, gut inflammation, motility disorders, postoperative ileus, purinergic signaling, Cytokines, Neuroglia, Inflammation, Intestine, Small/physiopathology, Animals, Gliosis, Mice, Purinergic P2X Receptor Antagonists/pharmacology",
author = "Reiner Schneider and Patrick Leven and Tim Glowka and Ivan Kuzmanov and Mariola Lysson and Bianca Schneiker and Anna Miesen and Younis Baqi and Claudia Spanier and Iveta Grants and Elvio Mazzotta and Egina Villalobos-Hernandez and Kalff, {J{\"o}rg C.} and M{\"u}ller, {Christa E.} and Christofi, {Fedias L.} and Sven Wehner",
note = "Funding Information: The authors thank the Next Generation Sequencing Core Facility and the Institute for Genomic Statistics and Bioinformatics of the University Clinics Bonn for supporting the RNA‐Seq analysis. The authors thank the Flow Cytometry Core Facility of the University Clinics Bonn for supporting the isolation of tdTomato EGCs. The sniffer cells (HEK mixed clone 228) were a gift from Dr. Terrance Egan, Saint Louis University to Fievos L. Christofi, The Ohio State University. The gpSox10 antibody was a kind gift of Professor Wegner, University of Erlangen. NIDDKNIHR01DK113943 to Dr. Fievos L. Christofi, an NCI Cost shared resource grant P30LA16058 for the molecular core facility in the College of Medicine, The Ohio State University. This publication was supported by a personnel grant of the German research council (DFG) to SW (WE4204/3‐1), BonnNI (Q‐611.0754), and the ImmunoSensation Cluster of Excellence (EXC 2151–390873048). + 2 Funding Information: The authors thank the Next Generation Sequencing Core Facility and the Institute for Genomic Statistics and Bioinformatics of the University Clinics Bonn for supporting the RNA-Seq analysis. The authors thank the Flow Cytometry Core Facility of the University Clinics Bonn for supporting the isolation of tdTomato+ EGCs. The sniffer cells (HEK mixed clone 228) were a gift from Dr. Terrance Egan, Saint Louis University to Fievos L. Christofi, The Ohio State University. The gpSox10 antibody was a kind gift of Professor Wegner, University of Erlangen. NIDDKNIHR01DK113943 to Dr. Fievos L. Christofi, an NCI Cost shared resource grant P30LA16058 for the molecular core facility in the College of Medicine, The Ohio State University. This publication was supported by a personnel grant of the German research council (DFG) to SW (WE4204/3-1), BonnNI (Q-611.0754), and the ImmunoSensation2 Cluster of Excellence (EXC 2151?390873048). Publisher Copyright: {\textcopyright} 2020 The Authors. Published under the terms of the CC BY 4.0 license",
year = "2021",
month = jan,
day = "11",
doi = "10.15252/emmm.202012724",
language = "English",
volume = "13",
journal = "EMBO Molecular Medicine",
issn = "1757-4676",
publisher = "Wiley-Blackwell",
number = "1",
}
