Inhibition of METTL3 in macrophages provides protection against intestinal inflammation

Huilong Yin; Zhuan Ju; Xiang Zhang; Wenjie Zuo; Yuhang Yang; Minhua Zheng; Xiaofang Zhang; Yuning Liu; Yingran Peng; Ying Xing; Angang Yang; Rui Zhang

doi:10.1038/s41423-024-01156-8

Inhibition of METTL3 in macrophages provides protection against intestinal inflammation

Cell Mol Immunol. 2024 Apr 22. doi: 10.1038/s41423-024-01156-8. Online ahead of print.

Authors

Huilong Yin^#^{1

2

3}, Zhuan Ju^#^{1

4

5

6}, Xiang Zhang^#⁵, Wenjie Zuo^#^{1

2

3}, Yuhang Yang^{1

2

3}, Minhua Zheng⁶, Xiaofang Zhang⁵, Yuning Liu^{1

2

3}, Yingran Peng⁵, Ying Xing⁷, Angang Yang⁸, Rui Zhang^{9

10}

Affiliations

¹ Henan Key Laboratory of Immunology and Targeted Therapy, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China.
² Molecular Immunology and Immunotherapy Laboratory, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China.
³ Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China.
⁴ State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China.
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.
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.
⁷ Department of Endocrinology, Xi'an Daxing Hospital, Xi'an, Shaanxi, 710000, China.
⁸ State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. agyang@fmmu.edu.cn.
⁹ State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, 710032, China. ruizhang@fmmu.edu.cn.
¹⁰ 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. ruizhang@fmmu.edu.cn.

^# Contributed equally.

PMID: 38649449
DOI: 10.1038/s41423-024-01156-8

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.

Keywords: Colitis; Glucose metabolism; Macrophage; N6-methyladenosine modification.

Abstract

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