000 02511 am a22003013u 4500
042 _adc
100 1 0 _aLindholm, Håvard T.
_eauthor
_92726
700 1 0 _aParmar, Naveen
_eauthor
_92727
700 1 0 _aDrurey, Claire
_eauthor
_92728
700 1 0 _aPoveda, Marta Campillo
_eauthor
_92729
700 1 0 _aVornewald, Pia
_eauthor
_92730
700 1 0 _aOstrop, Jenny
_eauthor
_92731
700 1 0 _aDíez-Sanchez, Alberto
_eauthor
_92732
700 1 0 _aMaizels, Rick M.
_eauthor
_92733
700 1 0 _aOudhoff, Menno J.
_eauthor
_92734
245 0 0 _aBMP-signaling in the intestinal epithelium drives a critical feedback loop to restrain IL-13-driven tuft cell hyperplasia
260 _c2022-05-13.
500 _a/pmc/articles/PMC7614132/
500 _a/pubmed/35559665
520 _aThe intestinal tract is a common site for different 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 immune-type specific cytokines such as IFNγ, IL-13 and IL-22. Here, we study intestinal epithelial immune responses using organoid image analysis based on a convolutional neural network, transcriptomic analysis, and in vivo infection models. We find that IL-22 and IL-13 both induce genes associated with goblet cells, but their phenotypes are dichotomous. Moreover, only IL-13 driven goblet cells are associated with classical NOTCH signaling. We further show that IL-13 induces BMP signaling, which acts in a negative feedback loop in immune type 2 driven tuft cell hyperplasia. This is associated with inhibiting Sox4 expression to putatively limit the tuft progenitor population. Blocking BMP signaling with the ALK2 inhibitor DMH1 interrupts the feedback loop, resulting in greater tuft cell numbers both in vitro and in vivo after infection with Nippostrongylus brasiliensis. Taken together, these novel aspects of cytokine effector responses reveal an unexpected and critical role for BMP signaling in type 2 immunity, which can be exploited to tailor epithelial immune responses.
540 _a
540 _ahttps://creativecommons.org/licenses/by/4.0/This work is licensed under a CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/) International license.
546 _aen
690 _aArticle
655 7 _aText
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786 0 _nSci Immunol
856 4 1 _uhttp://dx.doi.org/10.1126/sciimmunol.abl6543
_zConnect to this object online.
999 _c2350
_d2350