Enteric nervous system-derived VIP restrains differentiation of LGR5+ stem cells toward the secretory lineage impeding type 2 immune programs.
Type: article
Abstract: Barrier homeostasis relies on a finely tuned interplay between the immune system, epithelial cells and commensal microbiota. Beyond these regulators, the enteric nervous system has recently emerged as a central hub coordinating intestinal immune responses, although its role in epithelial differentiation has remained largely unexplored. Here, we identify a neuroepithelial circuit in which vasoactive intestinal peptide (VIP)-positive enteric neurons act on VIPR1+ epithelial stem cells to restrain both their proliferation and secretory lineage differentiation. Disruption of this pathway leads to an expansion of tuft cells, enhanced interleukin (IL)-25 production, activation of group 2 innate lymphoid cells (ILC2s) and induction of a type 2 immune response resembling worm expulsion. This phenotype occurs independently of the microbiota but is modulated by the IL-25R-ILC2-IL-13 axis and dietary solid food intake. Our findings expose the enteric nervous system as a critical regulator of epithelial fate decisions and immune balance, complementing established mechanisms that safeguard barrier integrity and mucosal homeostasis.
DOI: 10.48620/92705
Authors: Jakob, Manuel O., Sterczyk, Nele, Boulekou, Sotiria, Forster, Patrycja M, Barleben, Luisa, Alzain, Nadra, Jarick, Katja J, Pirzgalska, Roksana M, Raposo, Bruno, Hansson, Karl, Nyström, Elisabeth E L, Gondrand, Aurelia, González-Acera, Miguel, Leclère, Pierre S, Lapson, Marlen S, Poggenseier, Sarah, Deshpande, Divija, Velleman, Laura, Breiderhoff, Tilman, Brunkhorst, Max Felix, Schüle, Anton M, Guerra, Gabriela M, Durek, Pawel, Mashreghi, Mir-Farzin, Kühl, Anja A, Chu, Coco, Schneider, Christoph, Weidinger, Carl, Siegmund, Britta, Nordmann, Thierry M, Voehringer, David, Patankar, Jay V, Becker, Christoph, Birchenough, George M H, Veiga-Fernandes, Henrique, Kolesnichenko, Marina, Diefenbach, Andreas, Ronchi, Francesca, Klose, Christoph S N
Language: English
Topic: IL-33, ST2, and ILC Pathways
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7107952633
Cites:
Cited by:
Related to: