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Inhibition of METTL3 in macrophages provides protection against intestinal inflammation

Cellular & Molecular Immunology (2024)Cite this article

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Abstract

Inflammatory bowel disease (IBD) is prevalent, and no satisfactory therapeutic options are available because the mechanisms underlying its development are poorly understood. In this study, we discovered that increased expression of methyltransferase-like 3 (METTL3) in macrophages was correlated with the development of colitis and that depletion of METTL3 in macrophages protected mice against dextran sodium sulfate (DSS)-induced colitis. Mechanistic characterization indicated that METTL3 depletion increased the YTHDF3-mediated expression of phosphoglycolate phosphatase (PGP), which resulted in glucose metabolism reprogramming and the suppression of CD4+ T helper 1 (Th1) cell differentiation. Further analysis revealed that glucose metabolism contributed to the ability of METTL3 depletion to ameliorate colitis symptoms. In addition, we developed two potent small molecule METTL3 inhibitors, namely, F039-0002 and 7460-0250, that strongly ameliorated DSS-induced colitis. Overall, our study suggests that METTL3 plays crucial roles in the progression of colitis and highlights the potential of targeting METTL3 to attenuate intestinal inflammation for the treatment of colitis.

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Data availability

The mRNA sequencing data generated during this study have been deposited in the GEO database under the accession number GSE217269. All the data in this article are available from the corresponding authors upon reasonable request.

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Acknowledgements

We are grateful to Mrs. Fangli Gao from the Fourth Military Medical University for the careful breeding and reproduction of the mice. This study was supported by grants from the National Natural Science Foundation of China (grants 81630069 and 31771439 to YAG, 82173046 to ZR, and 31801128 to YHL, and 82173162 to ZX), the Program for Ph.D. Starting Research Funding from Xinxiang Medical University (grant 505249 to YHL), the Fund of State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers (grant CBSKL2022KF03 to YHL), and the National Key Research and Development Program (grant 2016YFC1303200 to ZR). The funders had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.

Author information

Author notes

  1. These authors contributed equally: Huilong Yin, Zhuan Ju, Xiang Zhang, Wenjie Zuo.

  2. These authors jointly supervised this work: Angang Yang, Rui Zhang.

Authors and Affiliations

  1. Henan Key Laboratory of Immunology and Targeted Therapy, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China

    Huilong Yin, Zhuan Ju, Wenjie Zuo, Yuhang Yang & Yuning Liu

  2. Molecular Immunology and Immunotherapy Laboratory, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China

    Huilong Yin, Wenjie Zuo, Yuhang Yang & Yuning Liu

  3. Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China

    Huilong Yin, Wenjie Zuo, Yuhang Yang & Yuning Liu

  4. State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Immunology, Fourth Military Medical University, Xi’an, Shaanxi, 710032, China

    Zhuan Ju, Angang Yang & Rui Zhang

  5. State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi’an, Shaanxi, 710032, China

    Zhuan Ju, Xiang Zhang, Xiaofang Zhang, Yingran Peng & Rui Zhang

  6. State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi’an, Shaanxi, 710032, China

    Zhuan Ju & Minhua Zheng

  7. Department of Endocrinology, Xi’an Daxing Hospital, Xi’an, Shaanxi, 710000, China

    Ying Xing

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  1. Huilong Yin
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Contributions

HLY, ZJ, XZ, RZ and AGY conceived the research, designed the study, interpreted the data and wrote the manuscript; HLY, ZJ, XZ, WJZ, YHY, MHZ, XFZ, YNL and YRP performed the experiments; HLY, ZJ, XZ and YX analyzed the data; and RZ and AGY are the co-senior authors who directed the research.

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Correspondence to Angang Yang or Rui Zhang.

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Yin, H., Ju, Z., Zhang, X. et al. Inhibition of METTL3 in macrophages provides protection against intestinal inflammation. Cell Mol Immunol (2024). https://doi.org/10.1038/s41423-024-01156-8

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