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

• Main Authors: Jiawei Li, Guowei Tu, Weitao Zhang, Yi Zhang, Xuepeng Zhang, Yue Qiu, Jiyan Wang, Tianle Sun, Tongyu Zhu, Cheng Yang, Ruiming Rong
• Format: Article
• Language: English
• Published: Nature Publishing Group 2021-02-01
• Series: Cell Death and Disease
• Online Access: https://doi.org/10.1038/s41419-021-03448-7

Abstract 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−Ly6Chigh CD127+ M-MDSCs, which exerted a stronger immunosuppressive function compared to CD11b+Ly6G−Ly6Chigh 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.