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Activating transcription factor 5 (ATF5) controls intestinal tuft and goblet cell expansion upon succinate-induced type 2 immune responses in mice

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Abstract

Intestinal tuft cells, a chemosensory cell type in mucosal epithelia that secrete interleukin (IL)-25, play a pivotal role in type 2 immune responses triggered by parasitic infections. Tuft cell-derived IL-25 activates type 2 innate lymphoid cells (ILC2) to secrete IL-13, which, in turn, acts on intestinal stem or transient amplifying cells to expand tuft cells themselves and mucus-secreting goblet cells. However, the molecular mechanisms of tuft cell differentiation under type 2 immune responses remain unclear. The present study investigated the effects of the deletion of activating transcription factor 5 (ATF5) on the type 2 immune response triggered by succinate (a metabolite of parasites) in mice. ATF5 mRNAs were expressed in the small intestine, and the loss of the ATF5 gene did not affect the gross morphology of the tissue or the basal differentiation of epithelial cell subtypes. Succinate induced marked increases in tuft and goblet cell numbers in the ATF5-deficient ileum. Tuft cells in the ATF5-deficient ileum are assumed to be a subtype of intestinal tuft cells (Tuft-2 cells) marked by the transcription factor Spib. Exogenous IL-25 induced similar increases in tuft and goblet cell numbers in wild-type and ATF5-deficient ilea. IL-13 at a submaximal dose enhanced tuft cell differentiation more in ATF5-deficient than in wild-type intestinal organoids. These results indicate that the loss of ATF5 enhanced the tuft cell-ILC2 type 2 immune response circuit by promoting tuft cell differentiation in the small intestine, suggesting its novel regulatory role in immune responses against parasitic infections.

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Data availability

The datasets generated and/or analyzed in this study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Dr. Kazuma Tomizuka for help with intestinal organoid cultures. We are grateful to Ms. Yukino Deguchi, Ms. Nozomi Josaka, and Mr. Katsutoshi Katsumata for their support with the preparation of mouse intestinal tissues.

Funding

This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (grant number 22K08064).

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Authors and Affiliations

  1. Laboratory of Environmental Molecular Physiology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan

    Haruo Nakano, Ayano Hata, Usato Ishimura, Ryo Kosugi, Eina Miyamoto, Kota Nakamura, Takumi Muramatsu, Moe Ogasawara, Motohiro Yamada, Mariko Umemura, Shigeru Takahashi & Yuji Takahashi

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  1. Haruo Nakano
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  2. Ayano Hata
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  3. Usato Ishimura
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  12. Yuji Takahashi
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Contributions

HN conceived the study and designed the project with ST and YT. MU maintained the ATF5-deficient mouse line. HN, AH, UI, RK, EM, KN, TM, MO, and MY performed experiments and analyzed data. HN wrote the manuscript, and all authors approved the final version of the manuscript.

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Correspondence to Haruo Nakano.

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All mouse studies were approved by the Institutional Animal Experiment Committee of the university and were performed in accordance with institutional and governmental guidelines.

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Nakano, H., Hata, A., Ishimura, U. et al. Activating transcription factor 5 (ATF5) controls intestinal tuft and goblet cell expansion upon succinate-induced type 2 immune responses in mice. Cell Tissue Res 393, 343–355 (2023). https://doi.org/10.1007/s00441-023-03781-7

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  • DOI: https://doi.org/10.1007/s00441-023-03781-7

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