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

Science immunology - Tập 7 Số 71 - 2022
Håvard T. Lindholm1, N. Parmar1, Claire Drurey2, Marta Campillo Poveda2, Pia M. Vornewald1, Jenny Ostrop1, Alberto Díez-Sánchez1, Rick M. Maizels2, Menno J. Oudhoff1
1CEMIR -Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, NTNU -Norwegian University of Science and Technology, 7491 Trondheim, Norway
2Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunology and Inflammation, University of Glasgow, G12 8TA Glasgow, United Kingdom.

Tóm tắt

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.

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Science immunology

Tập 7 Số 71

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