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 “enter...
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doaj-f5469403716a46148ae5ebeaac3b0ffb2021-08-02T18:59:09ZengWileyEMBO Molecular Medicine1757-46761757-46842021-01-01131n/an/a10.15252/emmm.202012724A novel P2X2‐dependent purinergic mechanism of enteric gliosis in intestinal inflammationReiner Schneider0Patrick Leven1Tim Glowka2Ivan Kuzmanov3Mariola Lysson4Bianca Schneiker5Anna Miesen6Younis Baqi7Claudia Spanier8Iveta Grants9Elvio Mazzotta10Egina Villalobos‐Hernandez11Jörg C Kalff12Christa E Müller13Fedias L Christofi14Sven Wehner15Department of Surgery University of Bonn Bonn GermanyDepartment of Surgery University of Bonn Bonn GermanyDepartment of Surgery University of Bonn Bonn GermanyDepartment of Surgery University of Bonn Bonn GermanyDepartment of Surgery University of Bonn Bonn GermanyDepartment of Surgery University of Bonn Bonn GermanyDepartment of Surgery University of Bonn Bonn GermanyFaculty of Science Department of Chemistry Sultan Qaboos University Muscat OmanPharmaceutical Institute Pharmaceutical & Medical Chemistry University of Bonn Bonn GermanyDepartment of Anesthesiology Wexner Medical Center The Ohio State University Columbus OH USADepartment of Anesthesiology Wexner Medical Center The Ohio State University Columbus OH USADepartment of Anesthesiology Wexner Medical Center The Ohio State University Columbus OH USADepartment of Surgery University of Bonn Bonn GermanyPharmaceutical Institute Pharmaceutical & Medical Chemistry University of Bonn Bonn GermanyDepartment of Anesthesiology Wexner Medical Center The Ohio State University Columbus OH USADepartment of Surgery University of Bonn Bonn GermanyAbstract 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.https://doi.org/10.15252/emmm.202012724enteric nervous systemgut inflammationmotility disorderspostoperative ileuspurinergic signaling |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Reiner Schneider Patrick Leven Tim Glowka Ivan Kuzmanov Mariola Lysson Bianca Schneiker Anna Miesen Younis Baqi Claudia Spanier Iveta Grants Elvio Mazzotta Egina Villalobos‐Hernandez Jörg C Kalff Christa E Müller Fedias L Christofi Sven Wehner |
spellingShingle |
Reiner Schneider Patrick Leven Tim Glowka Ivan Kuzmanov Mariola Lysson Bianca Schneiker Anna Miesen Younis Baqi Claudia Spanier Iveta Grants Elvio Mazzotta Egina Villalobos‐Hernandez Jörg C Kalff Christa E Müller Fedias L Christofi Sven Wehner A novel P2X2‐dependent purinergic mechanism of enteric gliosis in intestinal inflammation EMBO Molecular Medicine enteric nervous system gut inflammation motility disorders postoperative ileus purinergic signaling |
author_facet |
Reiner Schneider Patrick Leven Tim Glowka Ivan Kuzmanov Mariola Lysson Bianca Schneiker Anna Miesen Younis Baqi Claudia Spanier Iveta Grants Elvio Mazzotta Egina Villalobos‐Hernandez Jörg C Kalff Christa E Müller Fedias L Christofi Sven Wehner |
author_sort |
Reiner Schneider |
title |
A novel P2X2‐dependent purinergic mechanism of enteric gliosis in intestinal inflammation |
title_short |
A novel P2X2‐dependent purinergic mechanism of enteric gliosis in intestinal inflammation |
title_full |
A novel P2X2‐dependent purinergic mechanism of enteric gliosis in intestinal inflammation |
title_fullStr |
A novel P2X2‐dependent purinergic mechanism of enteric gliosis in intestinal inflammation |
title_full_unstemmed |
A novel P2X2‐dependent purinergic mechanism of enteric gliosis in intestinal inflammation |
title_sort |
novel p2x2‐dependent purinergic mechanism of enteric gliosis in intestinal inflammation |
publisher |
Wiley |
series |
EMBO Molecular Medicine |
issn |
1757-4676 1757-4684 |
publishDate |
2021-01-01 |
description |
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. |
topic |
enteric nervous system gut inflammation motility disorders postoperative ileus purinergic signaling |
url |
https://doi.org/10.15252/emmm.202012724 |
work_keys_str_mv |
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