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Cell. 2020 Jan 9;180(1):50-63.e12. doi: 10.1016/j.cell.2019.12.016.

Enteric Nervous System-Derived IL-18 Orchestrates Mucosal Barrier Immunity.

Author information

1
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
2
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: ruaidhri_jackson@hms.harvard.edu.
3
Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich 8091, Switzerland; Institute of Molecular Cancer Research, University of Zurich, Zurich 8057, Switzerland.
4
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA.
5
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
6
Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich 8091, Switzerland.
7
Institute of Molecular Cancer Research, University of Zurich, Zurich 8057, Switzerland.
8
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; University of Vienna, Universitätsring 1, Wien 1010, Austria.
9
Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA.
10
Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
11
Program of Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA; Applied Mathematics Program, Yale University, New Haven, CT 06511, USA.
12
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: rnowarski@bwh.harvard.edu.
13
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT 06520, USA. Electronic address: richard.flavell@yale.edu.

Abstract

Mucosal barrier immunity is essential for the maintenance of the commensal microflora and combating invasive bacterial infection. Although immune and epithelial cells are thought to be the canonical orchestrators of this complex equilibrium, here, we show that the enteric nervous system (ENS) plays an essential and non-redundant role in governing the antimicrobial protein (AMP) response. Using confocal microscopy and single-molecule fluorescence in situ mRNA hybridization (smFISH) studies, we observed that intestinal neurons produce the pleiotropic cytokine IL-18. Strikingly, deletion of IL-18 from the enteric neurons alone, but not immune or epithelial cells, rendered mice susceptible to invasive Salmonella typhimurium (S.t.) infection. Mechanistically, unbiased RNA sequencing and single-cell sequencing revealed that enteric neuronal IL-18 is specifically required for homeostatic goblet cell AMP production. Together, we show that neuron-derived IL-18 signaling controls tissue-wide intestinal immunity and has profound consequences on the mucosal barrier and invasive bacterial killing.

KEYWORDS:

Salmonella; antimicrobial proteins; barrier immunity; colon; goblet cell; homeostasis; inflammasome; microbiota; mucosal immunology; neuroimmunology

PMID:
31923399
DOI:
10.1016/j.cell.2019.12.016

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