Suppression of YTHDF2 attenuates autoimmune hepatitis by expansion of myeloid-derived suppressor cells

Zhuwan Lyu; Bingyuan Huang; Jun Zhang; Qiwei Qian; Xiting Pu; Nana Cui; Yiyan Ou; Bo Li; Zhengrui You; Min Lian; Ruqi Tang; Weihua Chen; Zhicong Zhao; Jiajie Hou; M Eric Gershwin; Haiyan Zhang; Qiang Xia; Xiong Ma

doi:10.1016/j.jaut.2023.102993

Suppression of YTHDF2 attenuates autoimmune hepatitis by expansion of myeloid-derived suppressor cells

J Autoimmun. 2023 Feb:135:102993. doi: 10.1016/j.jaut.2023.102993. Epub 2023 Jan 13.

Authors

Zhuwan Lyu¹, Bingyuan Huang¹, Jun Zhang¹, Qiwei Qian¹, Xiting Pu¹, Nana Cui¹, Yiyan Ou¹, Bo Li¹, Zhengrui You¹, Min Lian¹, Ruqi Tang¹, Weihua Chen¹, Zhicong Zhao², Jiajie Hou³, M Eric Gershwin⁴, Haiyan Zhang⁵, Qiang Xia⁶, Xiong Ma⁷

Affiliations

¹ Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China.
² Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Transplantation, Shanghai, 200127, China.
³ Department of Liver Surgery, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
⁴ Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA.
⁵ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address: zhanghy2@sysucc.org.cn.
⁶ Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Transplantation, Shanghai, 200127, China. Electronic address: xiaqiang@medmail.com.cn.
⁷ Division of Gastroenterology and Hepatology, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China. Electronic address: maxiongmd@hotmail.com.

PMID: 36642058
DOI: 10.1016/j.jaut.2023.102993

Abstract

Background & aims: The N6-methyladenosine (m⁶A) reader YTH domain-containing family protein 2 (YTHDF2) is critically involved in a multiplicity of biological processes by mediating the degradation of m⁶A modified mRNAs. Based on our current understanding of this process, we hypothesized that YTHDF2 will play a role in the natural history and function of myeloid-derived suppressor cells (MDSC) and in particular in AIH.

Approach & results: We took advantage of YTHDF2 conditional knock-out mice to first address the phenotype and function of MDSCs by flow cytometry. Importantly, the loss of YTHDF2 resulted in a gradual elevation of MDSCs including PMN-MDSCs both in liver and ultimately in the BM. Notably, YTHDF2 deficiency in myeloid cells attenuated concanavalin (ConA)-induced liver injury, with enhanced expansion and chemotaxis to liver. Furthermore, MDSCs from Ythdf2^CKO mice had a greater suppressive ability to inhibit the proliferation of T cells. Using multi-omic analysis of m⁶A RNA immunoprecipitation (RIP) and mRNA sequencing, we noted RXRα as potential target of YTHDF2. Indeed YTHDF2-RIP-qPCR confirmed that YTHDF2 directly binds RXRα mRNA thus promoting degradation and decreasing gene expression. Finally, by IHC and immunofluorescence, YTHDF2 expression was significantly upregulated in the liver of patients with AIH which correlated with the degree of inflammation.

Conclusion: Suppression of YTHDF2 enhances the expansion, chemotaxis and suppressive function of MDSCs and our data reveals a unique therapeutical target in immune mediated hepatitis.

Keywords: Autoimmune hepatitis; Myeloid-derived suppressor cells; N6-methyladenosine; YTHDF2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Hepatitis, Autoimmune*
Mice
Myeloid Cells
Myeloid-Derived Suppressor Cells*
T-Lymphocytes
Transcription Factors / metabolism

Substances

Transcription Factors
YTHDF2 protein, mouse