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The neuropeptide VIP potentiates intestinal innate type 2 and type 3 immunity in response to feeding

Abstract

The nervous system and the immune system both rely on an extensive set of modalities to perceive and act on perturbations in the internal and external environments. During feeding, the intestine is exposed to nutrients that may contain noxious substances and pathogens. Here we show that Vasoactive Intestinal Peptide (VIP), produced by the nervous system in response to feeding, potentiates the production of effector cytokines by intestinal type 2 and type 3 innate lymphoid cells (ILC2s and ILC3s). Exposure to VIP alone leads to modest activation of ILCs, but strongly potentiates ILCs to concomitant or subsequent activation by the inducer cytokines IL-33 or IL-23, via mobilization of cAMP and energy by glycolysis. Consequently, VIP increases resistance to intestinal infection by the helminth Trichuris muris and the enterobacteria Citrobacter rodentium. These findings uncover a functional neuro-immune crosstalk unfolding during feeding that increases the reactivity of innate immunity necessary to face potential threats associated with food intake.

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Fig. 1: ILC2s and ILC3s express VIPR2 and closely associate with VIP+ nerve fibers in the small intestine.
Fig. 2: VIP synergizes with alarmins to activate ILC2s and ILC3s through cAMP and Ca2+ dependent pathways.
Fig. 3: Feeding induces rapid VIP release in the intestine.
Fig. 4: VIP potentiates the response of ILC2s and ILC3s to alarmins.
Fig. 5: VIP reinforces type 2 and type 3 ILC-mediated immunity against infection.

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Acknowledgements

We thank all members of the Microenvironment and Immunity unit, the Perception and Memory unit, and the Stroma, Inflammation and Tissue Repair unit, in particular Bernadette Polomack for mouse genotyping. We also thank Uwe Maskos, Fani Koukouli and David Digregorio for providing us VIPCre Mice, and Meinrad Busslinger for the Gata3GFP mice. We thank Pierre Bost for sharing its expertise on image analysis, Jacques Serizay for providing guidance in data visualization for Fig. 1, Christelle Ganneau and Sylvie Bay for sharing their expertise on peptides biochemistry as well as Martine Jacob and Catherine Fayolle for their precious technical support with mice. M.P. is a recipient of a fellowship from the French Ministère de l’Education Nationale et de la Recherche. This work was supported by Institut Pasteur, a seed grant from the Institut Pasteur Strategic Research Axis 3, INSERM, CNRS, the life insurance company “AG2R-La-Mondiale” and grant ANR-16-CE15-0021-01 from the Agence Nationale de la Recherche Scientifique. C.W. and A.K. were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC2151 – 390873048 and program grants from the DFG (SPP1937, WI 4554/1-1 and WI 4554/1-2).

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M.P., conceptualization, methodology, validation, formal analysis, investigation, writing—original draft, writing - review & editing, visualization, supervision; A.K., methodology, validation, formal analysis, investigation, review & editing, visualization; G.C., conceptualization, methodology, investigation; L.D., J.D., A.D., F.J., S.D., C.M., investigation; S.S., K.S., formal analysis; Y.B., resources; G.L., conceptualization, methodology, investigation, writing - original draft, writing—review & editing, supervision, funding acquisition; P.-M.L., C.W., conceptualization, methodology, writing—original draft, writing—review & editing, supervision, funding acquisition; G.E., conceptualization, methodology, writing—original draft, writing—review & editing, project administration, funding acquisition.

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Correspondence to Maud Pascal, Pierre-Marie Lledo or Gérard Eberl.

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G.E. is a deputy editor at Mucosal Immunology.

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Pascal, M., Kazakov, A., Chevalier, G. et al. The neuropeptide VIP potentiates intestinal innate type 2 and type 3 immunity in response to feeding. Mucosal Immunol 15, 629–641 (2022). https://doi.org/10.1038/s41385-022-00516-9

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