Journal Article

DZNE-2025-00315

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Macrophage-induced enteric neurodegeneration leads to motility impairment during gut inflammation.

Breßer, M. ; Siemens, K. D. ; Schneider, L. ; Lunnebach, J. E. ; Leven, P. ; Glowka, T. R. ; Oberländer, K.DZNE* ; De Domenico, E.DZNE* ; Schultze, J. L.DZNE* ; Schmidt, J. ; Kalff, J. C. ; Schneider, A.DZNE* ; Wehner, S. ; Schneider, R.

2025
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s44321-024-00189-w

Abstract: 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.

Keyword(s): Animals (MeSH) ; Macrophages: metabolism (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Gastrointestinal Motility (MeSH) ; Enteric Nervous System: pathology (MeSH) ; Enteric Nervous System: physiopathology (MeSH) ; Disease Models, Animal (MeSH) ; Inflammation: pathology (MeSH) ; Neurons: pathology (MeSH) ; Neurons: metabolism (MeSH) ; Mice, Inbred C57BL (MeSH) ; Male (MeSH) ; Mice, Knockout (MeSH) ; Enteric Neurons ; Macrophages ; Neuroimmune Interaction ; Postoperative Ileus ; Synaptic Damage

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Contributing Institute(s):

1. Translational Dementia Research (Bonn) (AG Schneider)
2. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)
3. Platform for Single Cell Genomics and Epigenomics (PRECISE)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)
3. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

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