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

• Published in: Cell death & disease Vol. 12; no. 2; p. 177
• Main Authors: Li, Jiawei, Tu, Guowei, Zhang, Weitao, Zhang, Yi, Zhang, Xuepeng, Qiu, Yue, Wang, Jiyan, Sun, Tianle, Zhu, Tongyu, Yang, Cheng, Rong, Ruiming
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12-02-2021; Springer Nature B.V; Nature Publishing Group
• Subjects: 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
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-03448-7

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.