Suppression of YTHDF2 attenuates autoimmune hepatitis by expansion of myeloid-derived suppressor cells. Issue 135 (February 2023)

• Record Type: Journal Article
• Authors: Lyu, Zhuwan; Huang, Bingyuan; Zhang, Jun; Qian, Qiwei; Pu, Xiting; Cui, Nana; Ou, Yiyan; Li, Bo; You, Zhengrui; Lian, Min; Tang, Ruqi; Chen, Weihua; Zhao, Zhicong; Hou, Jiajie; Gershwin, M. Eric; Zhang, Haiyan; Xia, Qiang; Ma, Xiong
• Is Part Of: Journal of autoimmunity. Issue 135(2023)
• Publication Date: 2023-02
• Subjects: YTHDF2 -- N6-methyladenosine -- Myeloid-derived suppressor cells -- Autoimmune hepatitis; AIH autoimmune hepatitis -- AILD autoimmune liver diseases -- ALT alanine aminotransferase -- ALKBH5 alkB homologue 5 -- ALP Alkaline Phosphatase -- AST aspartate aminotransferase -- BM bone marrow -- CEBP/β CCAAT enhancer binding protein beta -- ConA concanavalin A -- CMP common myeloid progenitor -- DC dendritic cell -- FTO fat mass and obesity-associated protein -- GGT gamma-glutamyl transpeptidase -- GM-CSF granulocyte-macrophage colony-stimulating factor -- GMP granulocyte-macrophage progenitor -- H&E hematoxylin and eosin -- HLA human leukocyte antigen -- ID1 differentiation 1 -- IL-6 interleukin-6 -- IRF8 interferon regulatory factor 8 -- LSK Lin-Sca-1+c-Kit+ -- LPS lipopolysaccharide -- m6A N6-methyladenosine -- MDSC myeloid-derived suppressor cell -- Mettl3 methyltransferase like 3 -- Mettl14 methyltransferase like 14 -- MEP megakaryocyte-erythroid progenitor -- NAFLD non-alcoholic fatty liver disease -- NK natural killer -- NOS nitric oxidesynthase -- PBC primary biliary cholangitis -- PI propidium iodide -- SPF specific pathogen free -- ROS reactive oxygen species -- RXR Retinoid X receptor -- SOCS3 suppressor of cytokine signaling 3 -- TUNEL terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling -- YTHDF 1/2/3 YTH domain-containing family protein 1/2/3; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2023.102993
• Languages: English
• ISSNs: 0896-8411

Abstract

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. Highlights: YTHDF2 is a critical regulator for maintaining the homeostasis between MDSCs and mature myeloid cells. Ythdf2-deficient MDSCs manifest increased expansive and suppressive function, leading to attenuation of immune-mediated liver injury. Suppression of YTHDF2 promotes the expansion and function of MDSCs primarily by decreasing degradation of RXRα transcripts. YTHDF2 expression is significantly upregulated in the liver of patients with AIH which correlates with the degree of inflammation.