Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Feb 3;11(2):79.
doi: 10.1038/s41419-020-2276-8.

Erythropoietin and its derivatives: from tissue protection to immune regulation

Bo Peng #  1 , Gangcheng Kong #  1 , Cheng Yang  2   3 , Yingzi Ming  4
Affiliations
Review

Erythropoietin and its derivatives: from tissue protection to immune regulation

Bo Peng et al. Cell Death Dis. .

Abstract

Erythropoietin (EPO) is an evolutionarily conserved hormone well documented for its erythropoietic role via binding the homodimeric EPO receptor (EPOR)2. In past decades, evidence has proved that EPO acts far beyond erythropoiesis. By binding the tissue-protective receptor (TPR), EPO suppresses proinflammatory cytokines, protects cells from apoptosis and promotes wound healing. Very recently, new data revealed that TPR is widely expressed on a variety of immune cells, and EPO could directly modulate their activation, differentiation and function. Notably, nonerythropoietic EPO derivatives, which mimic the structure of helix B within EPO, specifically bind TPR and show great potency in tissue protection and immune regulation. These small peptides prevent the cardiovascular side effects of EPO and are promising as clinical drugs. This review briefly introduces the receptors and tissue-protective effects of EPO and its derivatives and highlights their immunomodulatory functions and application prospects.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. The effects of EPO on macrophages.
EPO regulates the polarization of macrophages via shifting them to M2 phenotype and exerts anti-inflammatory effects. Activation of TLR on macrophages leads to upregulation of inflammatory mediators and polarization to M1 phenotype, which aggravates tissue injury. EPO shifts macrophages to M2 phenotype via EPOR/Jak2/STAT3/STAT6 signaling pathway in the presence of IL-4. Meanwhile, EPO inhibits NF-κB p65 activation via EPOR/Jak2/PI3K pathway. EPO also plays a vital role in clearing apoptotic cells and cell debris. S1P released from apoptotic cells and hypoxia upregulate EPO and EPOR expression via HIF complex. EPO signaling increases the levels of phagocytic receptors through PPARγ pathway and facilitates phagocytosis of apoptotic cells. EPO erythropoietin, TPR tissue-protective receptor, S1P sphingosine 1-phosphate, HIF hypoxia-inducible factor.
Fig. 2
Fig. 2. EPO suppresses the maturation of dendritic cells.
EPO binds TPR and then activates Jak2/STAT-3/SOCS1 pathway. SOCS1 inhibits LPS signaling cascade. In addition, EPO can decrease the expression of MHC-II and costimulatory molecules. EPO erythropoietin, TPR tissue-protective receptor, HO-1 heme oxygenase-1, MHC-II major histocompatibility complex class II.
Fig. 3
Fig. 3. The effects of EPO on T cells.
EPO directly promotes the proliferation of Treg but inhibits the expansion of Tconv through the molecular crosstalk with IL-2 pathway. EPO also upregulates TGF-β expression of APC via TPR, which induces Treg differentiation from naïve CD4 T cells. EPO erythropoietin, Treg regulatory T cells, Tconv conventional T cells, APC antigen-presenting cells, TPR tissue-protective receptor.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Brines M, Cerami A. The receptor that tames the innate immune response. Mol. Med. 2012;18:486–496. doi: 10.2119/molmed.2011.00414. - DOI - PMC - PubMed
    1. Krzyzanski W, Wyska E. Pharmacokinetics and pharmacodynamics of erythropoietin receptor in healthy volunteers. Naunyn Schmiedebergs Arch. Pharmacol. 2008;377:637–645. doi: 10.1007/s00210-007-0225-z. - DOI - PubMed
    1. Brines M, Cerami A. Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response. J. Intern. Med. 2008;264:405–432. doi: 10.1111/j.1365-2796.2008.02024.x. - DOI - PubMed
    1. Murphy JM, Young IG. IL-3, IL-5, and GM-CSF signaling: crystal structure of the human beta-common receptor. Vitam. Horm. 2006;74:1–30. doi: 10.1016/S0083-6729(06)74001-8. - DOI - PubMed
    1. Brines M, et al. Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc. Natl Acad. Sci. USA. 2004;101:14907–14912. doi: 10.1073/pnas.0406491101. - DOI - PMC - PubMed

Publication types