Erythropoietin and Its Derivatives: from Tissue Protection to Immune Regulation

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2020 Feb 5

PMID 32015330

Citations 51

Authors

Bo Peng

Gangcheng Kong

Cheng Yang

Yingzi Ming

Affiliations

Soon will be listed here.

Abstract

Erythropoietin (EPO) is an evolutionarily conserved hormone well documented for its erythropoietic role via binding the homodimeric EPO receptor (EPOR). 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.

Citing Articles

Influence of TMPRSS6 genotype on iron status parameters in stable COPD patients.

Trtica M, Novakovic I, Dopsaj V, Milenkovic B, Jankovic J, Dimic-Janjic S J Med Biochem. 2025; 44(1):129-140.

PMID: 39991164 PMC: 11846647. DOI: 10.5937/jomb0-52996.

Identifying iNOS and glycogen as biomarkers for degenerated cerebellar purkinje cells in autism spectrum disorder: Protective effects of erythropoietin and zinc sulfate.

Al-Garni A, Hosny S, Almasabi F, Shati A, Alzamil N, ShamsEldeen A PLoS One. 2025; 20(2):e0317695.

PMID: 39946495 PMC: 11824972. DOI: 10.1371/journal.pone.0317695.

Plasma Soluble Progenitor Cell Receptors as Biomarkers for Severe Anemia Among Malaria-Infected Pediatrics: A Prospective Study in Ghana.

Nkansah C, Appiah S, Osei-Boakye F, Appiah-Kubi E, Abbam G, Daud S Health Sci Rep. 2025; 8(2):e70460.

PMID: 39931259 PMC: 11808392. DOI: 10.1002/hsr2.70460.

Z-Ligustilide: A Potential Therapeutic Agent for Atherosclerosis Complicating Cerebrovascular Disease.

Shen L, Tian Q, Ran Q, Gan Q, Hu Y, Du D Biomolecules. 2025; 14(12.

PMID: 39766330 PMC: 11726876. DOI: 10.3390/biom14121623.

Haematometabolism rewiring in atherosclerotic cardiovascular disease.

Yvan-Charvet L, Barouillet T, Borowczyk C Nat Rev Cardiol. 2025; .

PMID: 39743562 DOI: 10.1038/s41569-024-01108-9.

References

Brines M, Cerami A . The receptor that tames the innate immune response. Mol Med. 2011; 18:486-96. PMC: 3356428. DOI: 10.2119/molmed.2011.00414. View

Krzyzanski W, Wyska E . Pharmacokinetics and pharmacodynamics of erythropoietin receptor in healthy volunteers. Naunyn Schmiedebergs Arch Pharmacol. 2007; 377(4-6):637-45. DOI: 10.1007/s00210-007-0225-z. View

Brines M, Cerami A . Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response. J Intern Med. 2008; 264(5):405-32. DOI: 10.1111/j.1365-2796.2008.02024.x. View

Murphy J, Young I . 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. View

Brines M, Grasso G, Fiordaliso F, Sfacteria A, Ghezzi P, Fratelli M . Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci U S A. 2004; 101(41):14907-12. PMC: 522054. DOI: 10.1073/pnas.0406491101. View

Coldewey S, Khan A, Kapoor A, Collino M, Rogazzo M, Brines M . Erythropoietin attenuates acute kidney dysfunction in murine experimental sepsis by activation of the β-common receptor. Kidney Int. 2013; 84(3):482-90. DOI: 10.1038/ki.2013.118. View

Foley L, Fullerton D, Mares J, Sungelo M, Weyant M, Cleveland Jr J . Erythropoietin's Beta Common Receptor Mediates Neuroprotection in Spinal Cord Neurons. Ann Thorac Surg. 2017; 104(6):1909-1914. DOI: 10.1016/j.athoracsur.2017.07.052. View

Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M . Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science. 2004; 305(5681):239-42. DOI: 10.1126/science.1098313. View

Brines M, Patel N, Villa P, Brines C, Mennini T, De Paola M . Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci U S A. 2008; 105(31):10925-30. PMC: 2504825. DOI: 10.1073/pnas.0805594105. View

10.

Yang C, Xu Z, Zhao Z, Li L, Zhao T, Peng D . A novel proteolysis-resistant cyclic helix B peptide ameliorates kidney ischemia reperfusion injury. Biochim Biophys Acta. 2014; 1842(11):2306-17. DOI: 10.1016/j.bbadis.2014.09.001. View

11.

Sautina L, Sautin Y, Beem E, Zhou Z, Schuler A, Brennan J . Induction of nitric oxide by erythropoietin is mediated by the {beta} common receptor and requires interaction with VEGF receptor 2. Blood. 2009; 115(4):896-905. DOI: 10.1182/blood-2009-04-216432. View

12.

Collino M, Thiemermann C, Cerami A, Brines M . Flipping the molecular switch for innate protection and repair of tissues: Long-lasting effects of a non-erythropoietic small peptide engineered from erythropoietin. Pharmacol Ther. 2015; 151:32-40. DOI: 10.1016/j.pharmthera.2015.02.005. View

13.

Brines M . Discovery of a master regulator of injury and healing: tipping the outcome from damage toward repair. Mol Med. 2014; 20 Suppl 1:S10-6. PMC: 4374522. DOI: 10.2119/molmed.2014.00167. View

14.

Ueba H, Brines M, Yamin M, Umemoto T, Ako J, Momomura S . Cardioprotection by a nonerythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin. Proc Natl Acad Sci U S A. 2010; 107(32):14357-62. PMC: 2922582. DOI: 10.1073/pnas.1003019107. View

15.

Moon C, Krawczyk M, Paik D, Coleman T, Brines M, Juhaszova M . Erythropoietin, modified to not stimulate red blood cell production, retains its cardioprotective properties. J Pharmacol Exp Ther. 2005; 316(3):999-1005. DOI: 10.1124/jpet.105.094854. View

16.

Patel N, Nandra K, Brines M, Collino M, Fred Wong W, Kapoor A . A nonerythropoietic peptide that mimics the 3D structure of erythropoietin reduces organ injury/dysfunction and inflammation in experimental hemorrhagic shock. Mol Med. 2011; 17(9-10):883-92. PMC: 3188881. DOI: 10.2119/molmed.2011.00053. View

17.

Cruz Navarro J, Pillai S, Ponce L, Van M, Goodman J, Robertson C . Endothelial nitric oxide synthase mediates the cerebrovascular effects of erythropoietin in traumatic brain injury. Front Immunol. 2014; 5:494. PMC: 4191322. DOI: 10.3389/fimmu.2014.00494. View

18.

Su K, Yu Y, Hou H, Zhao J, Kou Y, Cheng L . AMP-activated protein kinase mediates erythropoietin-induced activation of endothelial nitric oxide synthase. J Cell Physiol. 2011; 227(8):3053-62. DOI: 10.1002/jcp.23052. View

19.

Bernaudin M, Marti H, Roussel S, Divoux D, Nouvelot A, MacKenzie E . A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab. 1999; 19(6):643-51. DOI: 10.1097/00004647-199906000-00007. View

20.

Kuhrt D, Wojchowski D . Emerging EPO and EPO receptor regulators and signal transducers. Blood. 2015; 125(23):3536-41. PMC: 4458796. DOI: 10.1182/blood-2014-11-575357. View