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A novel P2X2‐dependent purinergic mechanism of enteric gliosis in intestinal inflammation

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 gliosi...

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Autores principales: Schneider, Reiner, Leven, Patrick, Glowka, Tim, Kuzmanov, Ivan, Lysson, Mariola, Schneiker, Bianca, Miesen, Anna, Baqi, Younis, Spanier, Claudia, Grants, Iveta, Mazzotta, Elvio, Villalobos‐Hernandez, Egina, Kalff, Jörg C, Müller, Christa E, Christofi, Fedias L, Wehner, Sven
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799361/
https://www.ncbi.nlm.nih.gov/pubmed/33332729
http://dx.doi.org/10.15252/emmm.202012724
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author Schneider, Reiner
Leven, Patrick
Glowka, Tim
Kuzmanov, Ivan
Lysson, Mariola
Schneiker, Bianca
Miesen, Anna
Baqi, Younis
Spanier, Claudia
Grants, Iveta
Mazzotta, Elvio
Villalobos‐Hernandez, Egina
Kalff, Jörg C
Müller, Christa E
Christofi, Fedias L
Wehner, Sven
author_facet Schneider, Reiner
Leven, Patrick
Glowka, Tim
Kuzmanov, Ivan
Lysson, Mariola
Schneiker, Bianca
Miesen, Anna
Baqi, Younis
Spanier, Claudia
Grants, Iveta
Mazzotta, Elvio
Villalobos‐Hernandez, Egina
Kalff, Jörg C
Müller, Christa E
Christofi, Fedias L
Wehner, Sven
author_sort Schneider, Reiner
collection PubMed
description 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.
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spelling pubmed-77993612021-01-15 A novel P2X2‐dependent purinergic mechanism of enteric gliosis in intestinal inflammation Schneider, Reiner Leven, Patrick Glowka, Tim Kuzmanov, Ivan Lysson, Mariola Schneiker, Bianca Miesen, Anna Baqi, Younis Spanier, Claudia Grants, Iveta Mazzotta, Elvio Villalobos‐Hernandez, Egina Kalff, Jörg C Müller, Christa E Christofi, Fedias L Wehner, Sven EMBO Mol Med Articles 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. John Wiley and Sons Inc. 2020-12-17 2021-01-11 /pmc/articles/PMC7799361/ /pubmed/33332729 http://dx.doi.org/10.15252/emmm.202012724 Text en © 2020 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Schneider, Reiner
Leven, Patrick
Glowka, Tim
Kuzmanov, Ivan
Lysson, Mariola
Schneiker, Bianca
Miesen, Anna
Baqi, Younis
Spanier, Claudia
Grants, Iveta
Mazzotta, Elvio
Villalobos‐Hernandez, Egina
Kalff, Jörg C
Müller, Christa E
Christofi, Fedias L
Wehner, Sven
A novel P2X2‐dependent purinergic mechanism of enteric gliosis in intestinal inflammation
title 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_short 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
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799361/
https://www.ncbi.nlm.nih.gov/pubmed/33332729
http://dx.doi.org/10.15252/emmm.202012724
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