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2025

Nat Immunol. 2025 Dec;26(12):2244-2255. doi: 10.1038/s41590-025-02326-0. Epub 2025 Nov 24.

Neuroepithelial VIP–VIPR1 interactions differentially control enteric type 1 and type 2 immunity

Roksana M Pirzgalska, Beatriz Henriques-Alves, Bruno Raposo, Eric de Sousa, Júlio Torres, Jaechan Ryu, Cristina Godinho-Silva, Miguel Rendas, Madalena Pereira, Inês Godinho, Hélder Ribeiro, Vasco Correia, Manuel O Jakob, Patrycja M Forster, Christoph Wilhelm, Christoph S N Klose, Ricardo Rio-Tinto, Verena M Link, Tânia Carvalho, Carlos M Minutti, Manuela Ferreira, Henrique Veiga-Fernandes

Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Research, Lisbon, Portugal. University of Coimbra, Center for Innovative Biomedicine and Biotechnology, Center for Neuroscience and Cell Biology, Coimbra, Portugal. Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Microbiology, Infectious Diseases and Immunology, Berlin, Germany. Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 5nstitute of Clinical Chemistry and Clinical Pharmacology. University Hospital Bonn, Bonn, Germany. Cluster of Excellence ImmunoPreCept, Charité - Universitätsmedizin Berlin, Berlin, Germany. Champalimaud Foundation. Champalimaud Centre for the Unknown. Champalimaud Clinical Center, Lisbon, Portugal. Metaorganism Immunity Section, Laboratory of Host Immunity and Microbiome, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.

Service type: Knockout mice

Abstract

The nervous and immune systems cooperate to regulate mucosal barrier integrity. Nevertheless, whether enteric neurons establish neuroepithelial interactions to coordinate immunity remains elusive. Here, we identified neuroepithelial interactions that differentially control intestinal type 1 and type 2 immunity. Gut epithelial cells expressed vasoactive intestinal peptide (VIP) receptor 1 (VIPR1), and chemogenetic modulation of enteric VIPergic neurons led to altered epithelial-derived cytokines. Epithelial-intrinsic deletion of Vipr1 resulted in diminished type 1 immunity, including reduced type 1 alarmins and intraepithelial lymphocytes. In contrast, epithelial Vipr1 deficiency led to enhanced type 2 immunity, comprising increased type 2 alarmins, tuft cells and activated group 2 innate lymphoid cells. Disruption of neuroepithelial VIP-VIPR1 interactions resulted in increased susceptibility to invasive bacterial infection, which contrasted with enhanced resistance to parasite infection. Our work identifies a multi-tissue axis that controls type 1 and type 2 immunity, deciphering how neuroepithelial interactions distinctively set gut immunity programs.