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

被引:13
作者
Lyu, Zhuwan [1 ]
Huang, Bingyuan [1 ]
Zhang, Jun [1 ]
Qian, Qiwei [1 ]
Pu, Xiting [1 ]
Cui, Nana [1 ]
Ou, Yiyan [1 ]
Li, Bo [1 ]
You, Zhengrui [1 ]
Lian, Min [1 ]
Tang, Ruqi [1 ]
Chen, Weihua [1 ]
Zhao, Zhicong [2 ]
Hou, Jiajie [3 ,4 ]
Gershwin, M. Eric [5 ]
Zhang, Haiyan [4 ]
Xia, Qiang [2 ]
Ma, Xiong [1 ,6 ]
机构
[1] Shanghai Jiao Tong Univ, Renji Hosp, Shanghai Inst Digest Dis, Sch Med,Div Gastroenterol & Hepatol,NHC Key Lab Di, 145 Middle Shandong Rd, Shanghai 200001, Peoples R China
[2] Shanghai Jiao Tong Univ, Renji Hosp, Shanghai Inst Transplantat, Sch Med,Dept Liver Surg, Shanghai 200127, Peoples R China
[3] Sun Yat Sen Univ, Dept Liver Surg, Canc Ctr, Guangzhou 510060, Peoples R China
[4] Sun Yat Sen Univ, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China, Canc Ctr, Guangzhou, Peoples R China
[5] Univ Calif Davis, Dept Med Allergy & Clin Immunol, Div Rheumatol, Davis, CA USA
[6] Shanghai Jiao Tong Univ, Renji Hosp, Shanghai Inst Digest Dis, Sch Med, 145 Middle Shandong Rd, Shanghai 200001, Peoples R China
基金
中国国家自然科学基金;
关键词
YTHDF2; N6-methyladenosine; Myeloid -derived suppressor cells; Autoimmune hepatitis; MOLECULAR-MECHANISMS; EXPRESSION;
D O I
10.1016/j.jaut.2023.102993
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 Ythdf2CKO 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 RXR alpha as potential target of YTHDF2. Indeed YTHDF2-RIP-qPCR confirmed that YTHDF2 directly binds RXR alpha 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.
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页数:12
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