BMP signaling in the intestinal epithelium drives a critical feedback loop to restrain IL-13–driven tuft cell hyperplasia

Lindholm, H. T., Parmar, N., Drurey, C. , Campillo Poveda, M. , Vornewald, P. M., Ostrop, J., Díez-Sanchez, A., Maizels, R. M. and Oudhoff, M. J. (2022) BMP signaling in the intestinal epithelium drives a critical feedback loop to restrain IL-13–driven tuft cell hyperplasia. Science Immunology, 7(71), eabl6543. (doi: 10.1126/sciimmunol.abl6543) (PMID:35559665)

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The intestinal tract is a common site for various types of infections including viruses, bacteria, and helminths, each requiring specific modes of immune defense. The intestinal epithelium has a pivotal role in both immune initiation and effector stages, which are coordinated by lymphocyte cytokines such as IFNγ, IL-13, and IL-22. Here, we studied intestinal epithelial immune responses using organoid image analysis based on a convolutional neural network, transcriptomic analysis, and in vivo infection models. We found that IL-13 and IL-22 both induce genes associated with goblet cells, but the resulting goblet cell phenotypes are dichotomous. Moreover, only IL-13–driven goblet cells are associated with classical NOTCH signaling. We further showed that IL-13 induces the bone morphogenetic protein (BMP) pathway, which acts in a negative feedback loop on immune type 2–driven tuft cell hyperplasia. This is associated with inhibiting Sox4 expression to putatively limit the tuft cell progenitor population. Blocking ALK2, a BMP receptor, with the inhibitor dorsomorphin homolog 1 (DMH1) interrupted the feedback loop, resulting in greater tuft cell numbers both in vitro and in vivo after infection with Nippostrongylus brasiliensis. Together, this investigation of cytokine effector responses revealed an unexpected and critical role for the BMP pathway in regulating type 2 immunity, which can be exploited to tailor epithelial immune responses.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Drurey, Claire and Campillo Poveda, Dr Marta and Maizels, Professor Rick
Authors: Lindholm, H. T., Parmar, N., Drurey, C., Campillo Poveda, M., Vornewald, P. M., Ostrop, J., Díez-Sanchez, A., Maizels, R. M., and Oudhoff, M. J.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Science Immunology
Publisher:American Association for the Advancement of Science
ISSN (Online):2470-9468
Published Online:13 May 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Science Immunology 7(71): eabl6543
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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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
308411Molecular and Cellular Interactions in Helminth InfectionsRichard MaizelsWellcome Trust (WELLCOTR)219530/Z/19/ZIII - Parasitology
170547The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/ZIII - Parasitology