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

Abigail Jarret; Ruaidhrí Jackson; Coco Duizer; Marc E Healy; Jun Zhao; Joseph M Rone; Piotr Bielecki; Esen Sefik; Manolis Roulis; Tyler Rice; Kisha N Sivanathan; Ting Zhou; Angel G Solis; Hanna Honcharova-Biletska; Karelia Vélez; Saskia Hartner; Jun Siong Low; Rihao Qu; Marcel R de Zoete; Noah W Palm; Aaron M Ring; Achim Weber; Andreas E Moor; Yuval Kluger; Roni Nowarski; Richard A Flavell

doi:10.1016/j.cell.2019.12.016

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

Abigail Jarret, Ruaidhrí Jackson, Coco Duizer, Marc E Healy, Jun Zhao, Joseph M Rone, Piotr Bielecki, Esen Sefik, Manolis Roulis, Tyler Rice, Kisha N Sivanathan, Ting Zhou, Angel G Solis, Hanna Honcharova-Biletska, Karelia Vélez, Saskia Hartner, Jun Siong Low, Rihao Qu, Marcel R de Zoete, Noah W PalmAaron M Ring, Achim Weber, Andreas E Moor, Yuval Kluger, Roni Nowarski, Richard A Flavell

Yale University
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: [email protected].
Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich 8091, Switzerland; Institute of Molecular Cancer Research, University of Zurich, Zurich 8057, Switzerland.
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.
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich 8091, Switzerland.
Institute of Molecular Cancer Research, University of Zurich, Zurich 8057, Switzerland.
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; University of Vienna, Universitätsring 1, Wien 1010, Austria.
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.
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.
Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: [email protected].
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: [email protected].

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	50-63
Number of pages	26
Journal	Cell
Volume	180
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2019.12.016
Publication status	Published - 9 Jan 2020

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10.1016/j.cell.2019.12.016

Enteric Nervous System-DerivedFinal published version, 6.72 MBLicence: Taverne

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Jarret, A., Jackson, R., Duizer, C., Healy, M. E., Zhao, J., Rone, J. M., Bielecki, P., Sefik, E., Roulis, M., Rice, T., Sivanathan, K. N., Zhou, T., Solis, A. G., Honcharova-Biletska, H., Vélez, K., Hartner, S., Low, J. S., Qu, R., de Zoete, M. R., ... Flavell, R. A. (2020). Enteric Nervous System-Derived IL-18 Orchestrates Mucosal Barrier Immunity. Cell, 180(1), 50-63. https://doi.org/10.1016/j.cell.2019.12.016

@article{be993fd118994b60b389fa8af9797ab5,

title = "Enteric Nervous System-Derived IL-18 Orchestrates Mucosal Barrier Immunity",

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.",

author = "Abigail Jarret and Ruaidhr{\'i} Jackson and Coco Duizer and Healy, {Marc E} and Jun Zhao and Rone, {Joseph M} and Piotr Bielecki and Esen Sefik and Manolis Roulis and Tyler Rice and Sivanathan, {Kisha N} and Ting Zhou and Solis, {Angel G} and Hanna Honcharova-Biletska and Karelia V{\'e}lez and Saskia Hartner and Low, {Jun Siong} and Rihao Qu and {de Zoete}, {Marcel R} and Palm, {Noah W} and Ring, {Aaron M} and Achim Weber and Moor, {Andreas E} and Yuval Kluger and Roni Nowarski and Flavell, {Richard A}",

year = "2020",

month = jan,

day = "9",

doi = "10.1016/j.cell.2019.12.016",

language = "English",

volume = "180",

pages = "50--63",

journal = "Cell",

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Jarret, A, Jackson, R, Duizer, C, Healy, ME, Zhao, J, Rone, JM, Bielecki, P, Sefik, E, Roulis, M, Rice, T, Sivanathan, KN, Zhou, T, Solis, AG, Honcharova-Biletska, H, Vélez, K, Hartner, S, Low, JS, Qu, R, de Zoete, MR, Palm, NW, Ring, AM, Weber, A, Moor, AE, Kluger, Y, Nowarski, R & Flavell, RA 2020, 'Enteric Nervous System-Derived IL-18 Orchestrates Mucosal Barrier Immunity', Cell, vol. 180, no. 1, pp. 50-63. https://doi.org/10.1016/j.cell.2019.12.016

TY - JOUR

T1 - Enteric Nervous System-Derived IL-18 Orchestrates Mucosal Barrier Immunity

AU - Jarret, Abigail

AU - Jackson, Ruaidhrí

AU - Duizer, Coco

AU - Healy, Marc E

AU - Zhao, Jun

AU - Rone, Joseph M

AU - Bielecki, Piotr

AU - Sefik, Esen

AU - Roulis, Manolis

AU - Rice, Tyler

AU - Sivanathan, Kisha N

AU - Zhou, Ting

AU - Solis, Angel G

AU - Honcharova-Biletska, Hanna

AU - Vélez, Karelia

AU - Hartner, Saskia

AU - Low, Jun Siong

AU - Qu, Rihao

AU - de Zoete, Marcel R

AU - Palm, Noah W

AU - Ring, Aaron M

AU - Weber, Achim

AU - Moor, Andreas E

AU - Kluger, Yuval

AU - Nowarski, Roni

AU - Flavell, Richard A

PY - 2020/1/9

Y1 - 2020/1/9

N2 - 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.

AB - 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.

U2 - 10.1016/j.cell.2019.12.016

DO - 10.1016/j.cell.2019.12.016

M3 - Article

C2 - 31923399

SN - 0092-8674

VL - 180

SP - 50

EP - 63

JO - Cell

JF - Cell

IS - 1

ER -

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

Abstract

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