β-adrenergic signaling triggers enteric glia reactivity and acute enteric gliosis during surgery
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PROVIDER: PRJNA817245 | ENA |
REPOSITORIES: ENA
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Project 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 Sox10iCreERT2/Rpl22HA/+ 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 Sox10iCreERT2/JellyOPfl/+/Rpl22HA/+ 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 glia 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.
2023-11-15 | GSE198889 | GEO
Project description:IL-1 signaling in enteric glia initiates acute intestinal inflamation and modulates postoperative motility disturbances by triggering a reactive glial phenotype named enteric gliosis. Enteric glia modulate macrophage function and activity in this reactive state by releasing a unique panel of chemokines and cytokines. An enteric glia-selective knockout of this pathway ameliorates acute postoperative inflammation and prevents postoperative ileus.
2022-07-11 | GSE205610 | GEO
Project description:Purinergic signaling in enteric gliosis [Dataset EV1]
| PRJNA556859 | ENA
Project description:Purinergic signaling in enteric gliosis [Dataset EV2]
| PRJNA556860 | ENA
Project description:Enteric Glia treated with exATP
2020-11-15 | GSE134941 | GEO
Project description:Enteric glial cells are important players in the control of motility, intestinal barrier integrity and inflammation. During inflammation, they switch into a reactive phenotype enabling them to release inflammatory mediators, thereby shaping the inflammatory environment. While a plethora of well-established in vivo models exist, cell culture models necessary to decipher the mechanistic pathways of enteric glial reactivity are less well standardized. In particular, the composition of extracellular matrices (ECM) can massively affect the experimental outcome. Considering the growing number of studies involving primary enteric glial cells, a better understanding of their homeostatic and inflammatory in vitro culture conditions is needed. We examined the impact of different ECMs on enteric glial culture homeostasis and immune responsiveness. We used 3’ bulk mRNA sequencing to compare cultured cells with in vivo enteric glial transcriptomes isolated from Sox10iCreERT2Rpl22HA/+ mice. Transcriptional analysis revealed strong similarities between enteric glia on Matrigel and laminin with enrichment of gene sets supporting neuronal differentiation, while cells on poly-L-ornithine showed enrichment related to cell proliferation. Comparing cultured and in vivo enteric glial transcriptomes revealed a 50% overlap. IL-1β treatment showed distinct coating-dependent gene expression signatures, with an enrichment of genes related to myeloid and epithelial cell differentiation on Matrigel and laminin coatings, while poly-L-ornithine induced more gene sets related to lymphocyte differentiation. Together, changes in differentiation and immune activation of primary enteric glial cells proved a strong effect of the ECM. We identified Matrigel and laminin as pre-eminent substrates for murine enteric glial cultures. These new insights will help to standardize and improve enteric glial culture quality and reproducibility between studies in the future, allowing a better comparison of their functional role in enteric neuroinflammation.
2024-08-15 | GSE271114 | GEO
Project description:A novel P2X2-dependent purinergic mechanism of enteric gliosis in intestinal inflammation
| PRJNA627597 | ENA
Project description:A novel P2X2-dependent purinergic mechanism of enteric gliosis in intestinal inflammation
| PRJNA556856 | ENA
Project description:To identify the gene expression profile of enteric glia and assess the transcriptional similarity between enteric and extraenteric glia, we performed RNA sequencing analysis on PLP1-expressing cells in the mouse intestine. This analysis shows that enteric glia are transcriptionally unique and distinct from other cell types in the nervous system. Enteric glia express many genes characteristic of the myelinating glia, Schwann cells and oli- godendrocytes, although there is no evidence of myelination in the murine ENS. Total RNA expression profiles of PLP1 expressing enteric glial cells (GFP+) and non-glial cells (GFP-negative) were obtained from the ileum and colon of juvenile PLP1-eGFP transgenic mice.
2015-09-01 | E-GEOD-72560 | biostudies-arrayexpress
Project description:Tissue maintenance and repair depend on the integrated activity of multiple cell types. Whereas the contributions of epithelial, immune and stromal cells in intestinal tissue integrity are well understood, the role of intrinsic neuroglia networks remains largely unknown. Here, we uncover pivotal roles of enteric glial cells (EGCs) in intestinal homeostasis, immunity and tissue repair. We demonstrate that infection of mice with Heligmosomoides polygyrus (H. poly) leads to enteric gliosis and upregulation of the interferon gamma (IFN-γ) gene signature. Single-cell transcriptomics of tunica muscularis (TM) showed that glia-specific abrogation of IFN-γ signaling leads to tissue-wide activation of pro-inflammatory transcriptional programs. In addition, disruption of the IFN-γ-EGC signaling axis enhanced the inflammatory and granulomatous response of TM to helminths. Mechanistically, we show that upregulation of Cxcl10 is an early immediate response of EGCs to IFN-γ signaling and provide evidence that this chemokine and the downstream amplification of IFN-γ signaling in the TM are required for a measured inflammatory response to helminths and resolution of granulomatous pathology. Our study demonstrates that IFN-γ signaling in enteric glia is central to intestinal homeostasis and reveals critical roles of the IFN-γ-EGC-Cxcl10 axis in immune response and tissue repair following infectious challenge. To characterize the response of enteric glia to helminth infection at single cell resolution, we next performed scRNAseq (C1 Fluidigm platform) of tdT+ cells from the TM of naïve and H. poly-infected mice.
2021-08-31 | GSE182715 | GEO