The IL-25-dependent tuft cell circuit driven by intestinal helminths requires macrophage migration inhibitory factor (MIF)

Varyani, F. et al. (2022) The IL-25-dependent tuft cell circuit driven by intestinal helminths requires macrophage migration inhibitory factor (MIF). Mucosal Immunology, 15(6), pp. 1243-1256. (doi: 10.1038/s41385-022-00496-w) (PMID:35288645)

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Macrophage migration inhibitory factor (MIF) is a key innate immune mediator with chemokine- and cytokine-like properties in the inflammatory pathway. While its actions on macrophages are well-studied, its effects on other cell types are less understood. Here we report that MIF is required for expansion of intestinal tuft cells during infection with the helminth Nippostrongylus brasiliensis. MIF-deficient mice show defective innate responses following infection, lacking intestinal epithelial tuft cell hyperplasia or upregulation of goblet cell RELMβ, and fail to expand eosinophil, type 2 innate lymphoid cell (ILC2) and macrophage (M2) populations. Similar effects were observed in MIF-sufficient wild-type mice given the MIF inhibitor 4-IPP. MIF had no direct effect on epithelial cells in organoid cultures, and MIF-deficient intestinal stem cells could generate tuft cells in vitro in the presence of type 2 cytokines. In vivo the lack of MIF could be fully compensated by administration of IL-25, restoring tuft cell differentiation and goblet cell expression of RELM-β, demonstrating its requirement upstream of the ILC2-tuft cell circuit. Both ILC2s and macrophages expressed the MIF receptor CXCR4, indicating that MIF may act as an essential co-factor on both cell types to activate responses to IL-25 in helminth infection.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Drurey, Claire and Varyani, Dr Fumi and White, Dr Madeleine and Campillo Poveda, Dr Marta and Rasid, Dr Orhan and Maizels, Professor Rick and Smyth, Dr Danielle
Creator Roles:
Varyani, F.Investigation, Formal analysis, Writing – original draft, Writing – review and editing
Drurey, C.Investigation
Rasid, O.Investigation
Smyth, D. J.Investigation
Maizels, R. M.Formal analysis, Writing – original draft, Writing – review and editing
Authors: Varyani, F., Löser, S., Filbey, K. J., Harcus, Y., Drurey, C., Poveda, M. C., Rasid, O., White, M. P.J., Smyth, D. J., Gerbe, F., Jay, P., and Maizels, R. M.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Mucosal Immunology
Publisher:Springer Nature
ISSN (Online):1935-3456
Published Online:14 March 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Mucosal Immunology 15(6): 1243-1256
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173801Helminths and the Immune System: Regulation, Regulators and ImmunityRichard MaizelsWellcome Trust (WELLCOTR)106122/A/14/ZInstitute of Infection, Immunity & Inflammation
170547The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/ZIII - Parasitology