TY - JOUR
T1 - The IL-25-dependent tuft cell circuit driven by intestinal helminths requires macrophage migration inhibitory factor (MIF)
AU - Varyani, Fumi
AU - Löser, Stephan
AU - Filbey, Kara J.
AU - Harcus, Yvonne
AU - Drurey, Claire
AU - Poveda, Marta Campillo
AU - Rasid, Orhan
AU - White, Madeleine P. J.
AU - Smyth, Danielle J.
AU - Gerbe, François
AU - Jay, Philippe
AU - Maizels, Rick M.
N1 - Funding Information:
We thank Nicola Britton, Claire Ciancia and Anne-Marie Donachie for excellent technical assistance. The authors gratefully acknowledge the Flow Core Facility and Glasgow Imaging Facility, University of Glasgow for their support and assistance. This work was supported by the Wellcome Trust through an Investigator Award to RMM (Ref 106122), the Edinburgh Clinical Academic Track (Ref 107490) and the Wellcome Trust core-funded Wellcome Centre for Integrative Parasitology (Ref: 104111).
Copyright:
© 2022, The Author(s).
PY - 2022/4
Y1 - 2022/4
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85126262777
U2 - 10.1038/s41385-022-00496-w
DO - 10.1038/s41385-022-00496-w
M3 - Article
C2 - 35288645
AN - SCOPUS:85126262777
SN - 1933-0219
VL - 15
SP - 1243
EP - 1256
JO - Mucosal Immunology
JF - Mucosal Immunology
IS - 6
ER -