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β-adrenergic signaling triggers enteric glial reactivity and acute enteric gliosis during surgery
BACKGROUND: Enteric glia contribute to the pathophysiology of various intestinal immune-driven diseases, such as postoperative ileus (POI), a motility disorder and common complication after abdominal surgery. Enteric gliosis of the intestinal muscularis externa (ME) has been identified as part of PO...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10631040/ https://www.ncbi.nlm.nih.gov/pubmed/37941007 http://dx.doi.org/10.1186/s12974-023-02937-0 |
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author | Leven, Patrick Schneider, Reiner Schneider, Linda Mallesh, Shilpashree Vanden Berghe, Pieter Sasse, Philipp Kalff, Jörg C. Wehner, Sven |
author_facet | Leven, Patrick Schneider, Reiner Schneider, Linda Mallesh, Shilpashree Vanden Berghe, Pieter Sasse, Philipp Kalff, Jörg C. Wehner, Sven |
author_sort | Leven, Patrick |
collection | PubMed |
description | BACKGROUND: Enteric glia contribute to the pathophysiology of various intestinal immune-driven diseases, such as postoperative ileus (POI), a motility disorder and common complication after abdominal surgery. Enteric gliosis of the intestinal muscularis externa (ME) has been identified as part of POI development. However, the glia-restricted responses and activation mechanisms are poorly understood. The sympathetic nervous system becomes rapidly activated by abdominal surgery. It modulates intestinal immunity, innervates all intestinal layers, and directly interfaces with enteric glia. We hypothesized that sympathetic innervation controls enteric glia reactivity in response to surgical trauma. METHODS: Sox10(iCreERT2)/Rpl22(HA/+) mice were subjected to a mouse model of laparotomy or intestinal manipulation to induce POI. Histological, protein, and transcriptomic analyses were performed to analyze glia-specific responses. Interactions between the sympathetic nervous system and enteric glia were studied in mice chemically depleted of TH(+) sympathetic neurons and glial-restricted Sox10(iCreERT2)/JellyOP(fl/+)/Rpl22(HA/+) mice, allowing optogenetic stimulation of β-adrenergic downstream signaling and glial-specific transcriptome analyses. A laparotomy model was used to study the effect of sympathetic signaling on enteric glia in the absence of intestinal manipulation. Mechanistic studies included adrenergic receptor expression profiling in vivo and in vitro and adrenergic agonism treatments of primary enteric glial cell cultures to elucidate the role of sympathetic signaling in acute enteric gliosis and POI. RESULTS: With ~ 4000 differentially expressed genes, the most substantial enteric glia response occurs early after intestinal manipulation. During POI, enteric glia switch into a reactive state and continuously shape their microenvironment by releasing inflammatory and migratory factors. Sympathetic denervation reduced the inflammatory response of enteric glia in the early postoperative phase. Optogenetic and pharmacological stimulation of β-adrenergic downstream signaling triggered enteric glial reactivity. Finally, distinct adrenergic agonists revealed β-1/2 adrenoceptors as the molecular targets of sympathetic–driven enteric glial reactivity. CONCLUSIONS: Enteric glia act as early responders during post-traumatic intestinal injury and inflammation. Intact sympathetic innervation and active β-adrenergic receptor signaling in enteric glia is a trigger of the immediate glial postoperative inflammatory response. With immune-activating cues originating from the sympathetic nervous system as early as the initial surgical incision, adrenergic signaling in enteric glia presents a promising target for preventing POI development. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02937-0. |
format | Online Article Text |
id | pubmed-10631040 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-106310402023-11-08 β-adrenergic signaling triggers enteric glial reactivity and acute enteric gliosis during surgery Leven, Patrick Schneider, Reiner Schneider, Linda Mallesh, Shilpashree Vanden Berghe, Pieter Sasse, Philipp Kalff, Jörg C. Wehner, Sven J Neuroinflammation Research BACKGROUND: Enteric glia contribute to the pathophysiology of various intestinal immune-driven diseases, such as postoperative ileus (POI), a motility disorder and common complication after abdominal surgery. Enteric gliosis of the intestinal muscularis externa (ME) has been identified as part of POI development. However, the glia-restricted responses and activation mechanisms are poorly understood. The sympathetic nervous system becomes rapidly activated by abdominal surgery. It modulates intestinal immunity, innervates all intestinal layers, and directly interfaces with enteric glia. We hypothesized that sympathetic innervation controls enteric glia reactivity in response to surgical trauma. METHODS: Sox10(iCreERT2)/Rpl22(HA/+) mice were subjected to a mouse model of laparotomy or intestinal manipulation to induce POI. Histological, protein, and transcriptomic analyses were performed to analyze glia-specific responses. Interactions between the sympathetic nervous system and enteric glia were studied in mice chemically depleted of TH(+) sympathetic neurons and glial-restricted Sox10(iCreERT2)/JellyOP(fl/+)/Rpl22(HA/+) mice, allowing optogenetic stimulation of β-adrenergic downstream signaling and glial-specific transcriptome analyses. A laparotomy model was used to study the effect of sympathetic signaling on enteric glia in the absence of intestinal manipulation. Mechanistic studies included adrenergic receptor expression profiling in vivo and in vitro and adrenergic agonism treatments of primary enteric glial cell cultures to elucidate the role of sympathetic signaling in acute enteric gliosis and POI. RESULTS: With ~ 4000 differentially expressed genes, the most substantial enteric glia response occurs early after intestinal manipulation. During POI, enteric glia switch into a reactive state and continuously shape their microenvironment by releasing inflammatory and migratory factors. Sympathetic denervation reduced the inflammatory response of enteric glia in the early postoperative phase. Optogenetic and pharmacological stimulation of β-adrenergic downstream signaling triggered enteric glial reactivity. Finally, distinct adrenergic agonists revealed β-1/2 adrenoceptors as the molecular targets of sympathetic–driven enteric glial reactivity. CONCLUSIONS: Enteric glia act as early responders during post-traumatic intestinal injury and inflammation. Intact sympathetic innervation and active β-adrenergic receptor signaling in enteric glia is a trigger of the immediate glial postoperative inflammatory response. With immune-activating cues originating from the sympathetic nervous system as early as the initial surgical incision, adrenergic signaling in enteric glia presents a promising target for preventing POI development. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-023-02937-0. BioMed Central 2023-11-08 /pmc/articles/PMC10631040/ /pubmed/37941007 http://dx.doi.org/10.1186/s12974-023-02937-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Leven, Patrick Schneider, Reiner Schneider, Linda Mallesh, Shilpashree Vanden Berghe, Pieter Sasse, Philipp Kalff, Jörg C. Wehner, Sven β-adrenergic signaling triggers enteric glial reactivity and acute enteric gliosis during surgery |
title | β-adrenergic signaling triggers enteric glial reactivity and acute enteric gliosis during surgery |
title_full | β-adrenergic signaling triggers enteric glial reactivity and acute enteric gliosis during surgery |
title_fullStr | β-adrenergic signaling triggers enteric glial reactivity and acute enteric gliosis during surgery |
title_full_unstemmed | β-adrenergic signaling triggers enteric glial reactivity and acute enteric gliosis during surgery |
title_short | β-adrenergic signaling triggers enteric glial reactivity and acute enteric gliosis during surgery |
title_sort | β-adrenergic signaling triggers enteric glial reactivity and acute enteric gliosis during surgery |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10631040/ https://www.ncbi.nlm.nih.gov/pubmed/37941007 http://dx.doi.org/10.1186/s12974-023-02937-0 |
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