IL-17RA-signaling in Lgr5+ intestinal stem cells induces expression of transcription factor ATOH1 to promote secretory cell lineage commitment

Lin, Xun; Gaudino, Stephen; Jang, Kyung Ku; Bahadur, Tej; Singh, Ankita; Banerjee, Anirban; Beaupre, Michael; Chu, Timothy; Wong, Hoi Tong; Kim, Chang-Kyung; Kempen, Cody; Axelrad, Jordan E.; Huang, Hanchun; Khalid, Saba; Shah, Vyom; Eskiocak, Onur; Parks, Olivia B.; Berisha, Artan; McAleer, Jeremy P.; Good, Misty; Hoshino, Miko; Blumberg, Richard S.; Bialkowska, Agnieszka B.; Gaffen, Sarah L.; Kolls, Jay K.; Yang, Vincent W.; Beyaz, Semir; Cadwell, Ken; Kumar, Perikala V.

doi:10.1016/j.immuni.2021.12.016

Cited by 40 publications

(29 citation statements)

References 72 publications

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“…Overall, our approach of stimulating intestinal organoids with cytokines has revealed that developmental pathways underlie the cellular composition changes that occur as part of immune responses taking place in the intestine. In support, a recent study showed that IL-17RA signaling in intestinal stem cells induces ATOH1, thereby inducing secretory cells through NOTCH signaling ( 49 ). These changes have been confirmed using relevant in vivo models of infection or inflammation.…”

Section: Discussionmentioning

confidence: 79%

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

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 79%

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

et al. 2022

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“…A recent publication showed that IL-17 signaling on intestinal epithelial cells promotes goblet cell differentiation. 41 To assess the role of Il17 signaling on the increased goblet cell numbers observed in il10 -Mut larvae, we analyzed the abundance of intestinal goblet cells in WT larvae injected with an in vitro-generated il17 ( il17a/f3 ) mRNA at 1-cell stage (Fig. 3e ).…”

Section: Resultsmentioning

confidence: 99%

Interleukin-10 regulates goblet cell numbers through Notch signaling in the developing zebrafish intestine

et al. 2022

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Cytokines are immunomodulatory proteins that orchestrate cellular networks in health and disease. Among these, interleukin (IL)-10 is critical for the establishment of intestinal homeostasis, as mutations in components of the IL-10 signaling pathway result in spontaneous colitis. Whether IL-10 plays other than immunomodulatory roles in the intestines is poorly understood. Here, we report that il10, il10ra, and il10rb are expressed in the zebrafish developing intestine as early as 3 days post fertilization. CRISPR/Cas9-generated il10-deficient zebrafish larvae showed an increased expression of pro-inflammatory genes and an increased number of intestinal goblet cells compared to WT larvae. Mechanistically, Il10 promotes Notch signaling in zebrafish intestinal epithelial cells, which in turn restricts goblet cell expansion. Using murine organoids, we showed that IL-10 modulates goblet cell frequencies in mammals, suggesting conservation across species. This study demonstrates a previously unappreciated IL-10-Notch axis regulating goblet cell homeostasis in the developing zebrafish intestine and may help explain the disease severity of IL-10 deficiency in the intestines of mammals.

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“…IκBζ possibly mediates the role of Lgr5 + stem cells in the IL-17-mediated development of secretory IEC lineages including Paneth cells. 49 …”

Section: Resultsmentioning

confidence: 99%

“…IκBζ possibly mediates the role of Lgr5 + stem cells in the IL-17-mediated development of secretory IEC lineages including Paneth cells. 49 Lack of IκBζ in IECs causes aberrant activation of IFN-γ signaling in the small intestine As the expansion of SFB was more prominent at the jejunum than the ileum in Nfkbiz fl/fl Vil1-Cre mice (Fig. 2), we reasoned that the lack of IκBζ in IECs may have a greater impact on gene expression in the jejunum.…”

Section: The Il-17r-iκbζ Axis Facilitates Restoration Of Paneth Cells...mentioning

confidence: 99%

IκBζ controls IL-17-triggered gene expression program in intestinal epithelial cells that restricts colonization of SFB and prevents Th17-associated pathologies

et al. 2022

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Control of gut microbes is crucial for not only local defense in the intestine but also proper systemic immune responses. Although intestinal epithelial cells (IECs) play important roles in cytokine-mediated control of enterobacteria, the underlying mechanisms are not fully understood. Here we show that deletion of IκBζ in IECs in mice leads to dysbiosis with marked expansion of segmented filamentous bacteria (SFB), thereby enhancing Th17 cell development and exacerbating inflammatory diseases. Mechanistically, the IκBζ deficiency results in decrease in the number of Paneth cells and impairment in expression of IL-17-inducible genes involved in IgA production. The decrease in Paneth cells is caused by aberrant activation of IFN-γ signaling and a failure of IL-17-dependent recovery from IFN-γ-induced damage. Thus, the IL-17R–IκBζ axis in IECs contributes to the maintenance of intestinal homeostasis by serving as a key component in a regulatory loop between the gut microbiota and immune cells.

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IL-17RA-signaling in Lgr5+ intestinal stem cells induces expression of transcription factor ATOH1 to promote secretory cell lineage commitment

Cited by 40 publications

References 72 publications

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

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

Interleukin-10 regulates goblet cell numbers through Notch signaling in the developing zebrafish intestine

IκBζ controls IL-17-triggered gene expression program in intestinal epithelial cells that restricts colonization of SFB and prevents Th17-associated pathologies

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