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, Xiong Ma
Abstract
Background & aims The N6-methyladenosine (m 6 A) reader YTH domain-containing family protein 2 (YTHDF2) is critically involved in a multiplicity of biological processes by mediating the degradation of m 6 A 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 m 6 A 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.