Journal Article

CHBP induces stronger immunosuppressive CD127+ M-MDSC via erythropoietin receptor

Yang, Cheng, Tu, Guowei, Qiu, Yue, Rong, Ruiming, Zhang, Yi, Zhang, Xuepeng, Li, Jiawei, Zhang, Weitao, Wang, Jiyan, Sun, Tianle, Zhu, Tongyu

2021

Overview

Erythropoietin (EPO) is not only an erythropoiesis hormone but also an immune-regulatory cytokine. The receptors of EPO (EPOR) 2 and tissue-protective receptor (TPR), mediate EPO’s immune regulation. Our group firstly reported a non-erythropoietic peptide derivant of EPO, cyclic helix B peptide (CHBP), which could inhibit macrophages inflammation and dendritic cells (DCs) maturation. As a kind of innate immune regulatory cell, myeloid-derived suppressor cells (MDSCs) share a common myeloid progenitor with macrophages and DCs. In this study, we investigated the effects on MDSCs differentiation and immunosuppressive function via CHBP induction. CHBP promoted MDSCs differentiate toward M-MDSCs with enhanced immunosuppressive capability. Infusion of CHBP-induced M-MDSCs significantly prolonged murine skin allograft survival compared to its counterpart without CHBP stimulation. In addition, we found CHBP increased the proportion of CD11b + Ly6G − Ly6C high CD127 + M-MDSCs, which exerted a stronger immunosuppressive function compared to CD11b + Ly6G − Ly6C high CD127 − M-MDSCs. In CHBP induced M-MDSCs, we found that EPOR downstream signal proteins Jak2 and STAT3 were upregulated, which had a strong relationship with MDSC function. In addition, CHBP upregulated GATA-binding protein 3 (GATA-3) protein translation level, which was an upstream signal of CD127 and regulator of STAT3. These effects of CHBP could be reversed if Epor was deficient. Our novel findings identified a new subset of M-MDSCs with better immunosuppressive capability, which was induced by the EPOR-mediated Jak2/GATA3/STAT3 pathway. These results are beneficial for CHBP clinical translation and MDSC cell therapy in the future.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 13/31 / 45/91 / 631/250/1854/2812 / 692/699/249/2510 / 96/31 / Animals / Antibodies / Biochemistry / Biomedical and Life Sciences / CD11b antigen / CD4-Positive T-Lymphocytes - immunology / CD4-Positive T-Lymphocytes - metabolism / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Cell Biology / Cell Culture / Cell Differentiation - drug effects / Cell therapy / Dendritic cells / Erythropoiesis / Erythropoietin / GATA-3 protein / GATA-binding protein / GATA3 Transcription Factor - metabolism / Graft Rejection - immunology / Graft Rejection - metabolism / Graft Rejection - prevention & control / Graft Survival - drug effects / Immunology / Immunoregulation / Immunosuppressive Agents - pharmacology / Interleukin-7 Receptor alpha Subunit - metabolism / Janus kinase 2 / Janus Kinase 2 - metabolism / Life Sciences / Macrophages / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / Mice, Knockout / Myeloid-Derived Suppressor Cells - drug effects / Myeloid-Derived Suppressor Cells - immunology / Myeloid-Derived Suppressor Cells - metabolism / Myeloid-Derived Suppressor Cells - transplantation / Peptides / Phenotype / Receptors, Erythropoietin - agonists / Receptors, Erythropoietin - metabolism / Signal Transduction / Skin Transplantation - adverse effects / Stat3 protein / STAT3 Transcription Factor - metabolism / Suppressor cells / Time Factors / Translation