![[feed]](/style/images/feed-icon-14x14.png){kind=icon}
Tools
Tools
| Item Type: | Article |
|---|---|
| Title: | Coordinated IFN-γ/TNF axis drives selective loss of activated enteric glia in inflammatory bowel diseases |
| Creators: |
Bubeck, Marvin, Penkert, Klara A.  ORCID: https://orcid.org/0000-0002-9948-533X, Limberger, Heidi, González Acera, Miguel, Plattner, Christina, Ziegler, Svenja, Muppirala, Anoohya, Forster, Patrycja, Jakob, Manuel, Gamez-Belmonte, Reyes, Erkert, Lena, Kulkarni, Subhash, Günther, Claudia, Atreya, Raja, Kühl, Anja A., Hegazy, Ahmed N., Hildner, Kai, Trajanoski, Zlatko, Siegmund, Britta, Neurath, Markus F., Rao, Meenakshi, Progatzky, Fränze, Lie, Dieter Chichung, Becker, Christoph, Romagnani, Chiara, Ludwig, Leif S. ORCID: https://orcid.org/0000-0002-2916-2164, Klose, Christoph S.N. and Patankar, Jay V.
|
| Abstract: | BACKGROUND AND AIMS: Enteric glial cells (EGCs) regulate gastrointestinal homeostasis and inflammation. While activated EGCs have been shown to support epithelial and immune balance in preclinical models, their functional status and turnover in inflammatory bowel diseases (IBD) remain poorly defined. This study aimed to identify EGC activation markers and assess their susceptibility to cytokine-driven death in IBD. METHODS: We analysed 390 intestinal samples from IBD patients using bulk and single-nucleus RNA sequencing and validated findings across public datasets comprising over 1,160 patients and 19,000 EGC transcriptomes. We used multiple mouse models of gut inflammation, reporter-based glial sorting, transcriptomics, and glia-specific Casp8 deletion to dissect mechanisms of EGC activation and death. Ex vivo stimulation of sorted EGCs was used to assess cytokine-specific effects. RESULTS: We identified novel IBD subtype- and location-specific EGC activation markers, including osteopontin (SPP1), enriched in ulcerative colitis. Single-nucleus and single-cell data revealed that activated EGC clusters selectively upregulate cell death signatures with IBD EGC displaying necroptosis via phosphorylation of MLKL. In mice, acute Th1/Th17-driven inflammation rapidly induced EGC activation and necroptosis, impairing intestinal motility. Ex vivo, IFN-γ and TNF co-stimulation, but not individual cytokines, induced MLKL-dependent necroptosis in EGCs. Casp8-deficient EGCs were hypersensitive to TNF-induced death, confirming a Caspase-8 -dependent survival checkpoint. CONCLUSION: A proportion of activated EGC are selectively eliminated in IBD via cytokine-mediated necroptosis, driven by a coordinated IFN-γ/TNF axis. This process compromises enteric glial support functions and may contribute to IBD-associated dysmotility. Targeting glial survival may represent a novel therapeutic avenue. |
| Keywords: | Enteric Glial Cells, Necroptosis, IFN-γ, TNF, Inflammatory Bowel Diseases, Animals, Mice |
| Source: | Cellular and Molecular Gastroenterology and Hepatology |
| ISSN: | 2352-345X |
| Publisher: | Elsevier / American Gastroenterological Association Institute |
| Page Range: | 101827 |
| Date: | 12 June 2026 |
| Additional Information: | Leif S. Ludwig and Ashley D. Sanders are members of the TRR241 IBDome Consortium. |
| Official Publication: | https://doi.org/10.1016/j.jcmgh.2026.101827 |
| PubMed: | View item in PubMed |
| Related to: |
Repository Staff Only: item control page
