Macrophage-induced enteric neurodegeneration leads to motility impairment during gut inflammation
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ABSTRACT:
PROVIDER: PRJNA1095896 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR28544517.fastq.gz | Fastqsanger.gz | |||
| SRR28544518.fastq.gz | Fastqsanger.gz | |||
| SRR28544519.fastq.gz | Fastqsanger.gz | |||
| SRR28544520.fastq.gz | Fastqsanger.gz | |||
| SRR28544521.fastq.gz | Fastqsanger.gz |
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Project description:Background: Current studies provide compelling evidence that the enteric nervous system and neighboring resident macrophages in the muscularis externa modulate neuroimmune processes in the gut after abdominal surgery. While substantial knowledge exists about macrophage-enteric glia interactions, the fate of enteric neurons, which have an indispensable role in gut homeostasis and gastrointestinal motility, has not been thoroughly investigated during enteric neuroinflammation. Therefore, we investigated the impact of enteric neuron-macrophage interactions on postoperative trauma and subsequent motility disturbances, i.e., postoperative ileus. Methods: Neuroinflammation and postoperative ileus were induced in various transgenic mice by surgical manipulation of the small intestine. We studied enteric neurons and macrophage-specific transcriptomes using bulk RNA-Seq in neuron-specific RiboTag mice and sorted CX3CR1-GFP+ macrophages. To investigate their intercellular communication, we treated CX3CR1-GFP+ mice with CSFR1-antibody to deplete macrophages and subsequently induce POI through surgical trauma. These mice were examined for gastrointestinal motility, immune cell infiltration, and neuronal function. Ultimately, we validated the murine data in human gut samples collected early and late during abdominal surgery to understand the impact of surgical manipulation on patients' enteric nervous system function. Results: We detected strong neuronal activation in the early postsurgical phase, followed, after 24h, by transcriptional signatures of neuronal proliferation, neuronal death, and synaptic degradation. Neuron-specific transcriptome analysis confirmed these changes and verified the neuronal responses to the inflammatory environment. Simultaneously, our study revealed a neurodegenerative profile in macrophage-specific transcriptomes during POI. Depletion of macrophages before surgical manipulation led to decreased neuronal death, less synaptic decay, and improved GI motility, emphasizing the essential role of macrophages in neurodegeneration during intestinal neuroinflammation. In human jejunal muscularis externa samples, taken at early and late stages of pancreatectomies, we detected reactive and dying neurons with dysregulated gene expression of synaptic signaling and neurogenic processes. Conclusion: Surgical trauma and acute intestinal inflammation activate enteric neurons and induce neurodegeneration with severe synaptic decay, predominantly mediated by resident macrophages. Future studies should focus on neuroprotective mechanisms to dampen neurodegeneration and promote faster recovery from postoperative inflammation and motility disturbances.
2024-12-31 | GSE263125 | GEO
Project description:Current studies pictured the enteric nervous system and macrophages as modulators of neuroimmune processes in the inflamed gut. Expanding this view, we investigated the impact of enteric neuron-macrophage interactions on postoperative trauma and subsequent motility disturbances, i.e., postoperative ileus. In the early postsurgical phase, we detected strong neuronal activation, followed by transcriptional and translational signatures indicating neuronal death and synaptic damage. Simultaneously, our study revealed neurodegenerative profiles in macrophage-specific transcriptomes after postoperative trauma. Validating the role of resident and monocyte-derived macrophages, we depleted macrophages by CSF-1R-antibodies and used CCR2-/- mice, known for reduced monocyte infiltration, in POI studies. Only CSF-1R-antibody-treated animals showed decreased neuronal death and lessened synaptic decay, emphasizing the significance of resident macrophages. In human gut samples taken early and late during abdominal surgery, we substantiated the mouse model data and found reactive and apoptotic neurons and dysregulation in synaptic genes, indicating a species' overarching mechanism. Our study demonstrates that surgical trauma activates enteric neurons and induces neurodegeneration, mediated by resident macrophages, introducing neuroprotection as an option for faster recovery after surgery.
| S-SCDT-10_1038-S44321-024-00189-W | biostudies-other
Project description:Current studies pictured the enteric nervous system and macrophages as modulators of neuroimmune processes in the inflamed gut. Expanding this view, we investigated the impact of enteric neuron-macrophage interactions on postoperative trauma and subsequent motility disturbances, i.e., postoperative ileus. In the early postsurgical phase, we detected strong neuronal activation, followed by transcriptional and translational signatures indicating neuronal death and synaptic damage. Simultaneously, our study revealed neurodegenerative profiles in macrophage-specific transcriptomes after postoperative trauma. Validating the role of resident and monocyte-derived macrophages, we depleted macrophages by CSF-1R-antibodies and used CCR2-/- mice, known for reduced monocyte infiltration, in POI studies. Only CSF-1R-antibody-treated animals showed decreased neuronal death and lessened synaptic decay, emphasizing the significance of resident macrophages. In human gut samples taken early and late during abdominal surgery, we substantiated the mouse model data and found reactive and apoptotic neurons and dysregulation in synaptic genes, indicating a species' overarching mechanism. Our study demonstrates that surgical trauma activates enteric neurons and induces neurodegeneration, mediated by resident macrophages, introducing neuroprotection as an option for faster recovery after surgery.
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Project description:Combat veterans from the Persian Gulf War have unexplained yet persistent impairment in colonic motility due to combat-related toxic exposures. Central to Gulf War-related toxic exposures was the unmitigated ingestion of Pyridostigmine bromide (PB). We previously developed a Gulf War Illness (GWI) mouse model, where acute PB exposure led to immediate disruptions in colonic motility. Here, we explore mechanisms by which acute enteric neuroinflammation produces peristent impairment in colonic motility. GWI mice were exposed to PB transiently, and allowed to recover with no exposures for 1 month. GWI mice had significantly increased amplitudes of colonic contraction and diminished nerve-stimulated colonic relaxation, compared to naive controls. Immunohistological characterization demonstrated persistent chronic damage in enteric neuronal network integrity, accompanied by a significant imbalance in excitatory and inhibitory motor neuronal populations. Inflammatory CD40+ tissue- resident macrophages were identified with enteric neural stem cells in GWI colons, with an increase in secreted inflammatory cytokines. Unbiased transcriptomic analysis corroborated peristent low grade enteric neuroinflammation, overall resulting in impaired repair and regeneration of neural circuity in GWI. Our learnings can be leveraged to design new regenerative therapies for Gulf War veterans, and broadly impact our understanding of severeal inflammatory disorders of the gut.
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Project description:Enteric glia are the predominant cell type in the enteric nervous system yet their identities and roles in gastrointestinal function are not well classified. Using our optimized single nucleus RNA-sequencing method, we identified distinct molecular classes of enteric glia and defined their morphological and spatial diversity. Our findings revealed a functionally specialized biosensor subtype of enteric glia that we call “hub cells.” Deletion of the mechanosensory ion channel PIEZO2 from adult enteric glial hub cells, but not other subtypes of enteric glia, led to defects in intestinal motility and gastric emptying in mice. These results provide insight into the multifaceted functions of different enteric glial cell subtypes in gut health and emphasize that therapies targeting enteric glia could advance the treatment of gastrointestinal diseases.
2023-09-08 | GSE232703 | GEO
Project description:Enteric glia are the predominant cell type in the enteric nervous system yet their identities and roles in gastrointestinal function are not well classified. Using an optimized single nucleus RNA-sequencing method, we identified distinct molecular classes of enteric glia and defined their morphological and spatial diversity. Our findings revealed a functionally specialized class of enteric glial cells that we call “hub cells.” Hub cells retain dual functionality: they generate neurons and glia and act as force transducers to regulate intestinal physiology. Deletion of the mechanosensory ion channel PIEZO2 from adult enteric glial hub cells, but not other subtypes of enteric glia, led to defects in intestinal motility and gastric emptying in mice. These results provide insight into the multifaceted functions of different enteric glial cell subtypes in gut health and emphasize that therapies targeting enteric glia could advance the treatment of gastrointestinal diseases.
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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:ATP6AP2 is an essential accessory component of the vacuolar H+ ATPase (V-ATPase) and has been associated with intellectual disabilities (ID) and Parkinsonism. ATP6AP2 has been implicated in several signaling pathways, but little is known about its role in the nervous system. To decipher its function in behaviour and cognition, we generated and characterized conditional ATP6AP2 Drosophila and mouse models in the nervous system. In Drosophila, knockdown of ATP6AP2 induced defective phototaxis and vacuolisation of photoreceptor neurons and pigment cells when deleted in eyes and alteration of short- and long-term memory when deleted in the mushroom body. In mouse, conditional Atp6ap2 deletion in glutamatergic neurons (Atp6ap2Camk2aCre/0 mice) caused increased spontaneous locomotor activity and altered memory for fear. Both Drosophila ATP6AP2 knockdown and Atp6ap2Camk2aCre/0 mice presented with presynaptic transmission defect, abnormal number and morphology of synapses, and alteration of axonal transport in fly. In addition, Atp6ap2Camk2aCre/0 mice showed autophagy defect leading to axonal and neuronal degeneration in the cortex and the hippocampus. Surprisingly, myelinisation of axons was affected in our mutant mice. In accordance with the identified phenotypes across species, genome-wide transcriptome profiling of Atp6ap2Camk2aCre/0 mouse hippocampi revealed dysregulated genes involved in myelination, action potential, membrane bound vesicles and adult behaviour. In summary, disruption of ATP6AP2 in mouse and fly leads to cognitive impairment and neurodegeneration, mimicking aspects of the neuropathology associated with ATP6AP2 mutations in humans. Our results identify ATP6AP2 as an essential gene for the nervous system. 4 samples, 2 wt and 2 Atp6ap2Camk2aCre/0
2015-09-22 | E-GEOD-67541 | biostudies-arrayexpress
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