Modulation of cellular stress response via the erythropoietin/CD131 heteroreceptor complex in mouse mesenchymal-derived cells
- 444 Downloads
Tissue-protective properties of erythropoietin (EPO) have let to the discovery of an alternative EPO signaling via an EPO-R/CD131 receptor complex which can now be specifically targeted through pharmaceutically designed short sequence peptides such as ARA290. However, little is still known about specific functions of alternative EPO signaling in defined cell populations. In this study, we investigated effects of signaling through EPO-R/CD131 complex on cellular stress responses and pro-inflammatory activation in different mesenchymal-derived phenotypes. We show that anti-apoptotic, anti-inflammatory effects of ARA290 and EPO coincide with the externalization of CD131 receptor component as an immediate response to cellular stress. In addition, alternative EPO signaling strongly modulated transcriptional, translational, or metabolic responses after stressor removal. Specifically, we saw that ARA290 was able to overcome a TNFα-mediated inhibition of transcription factor activation related to cell stress responses, most notably of serum response factor (SRF), heat shock transcription factor protein 1 (HSF1), and activator protein 1 (AP1). We conclude that alternative EPO signaling acts as a modulator of pro-inflammatory signaling pathways and likely plays a role in restoring tissue homeostasis.
• Erythropoietin (EPO) triggers an alternative pathway via heteroreceptor EPO/CD131.
• ARA290 peptide specifically binds EPO/CD131 but not the canonical EPO/EPO receptor.
• Oxidative stress and inflammation promote cell surface expression of CD131.
• ARA290 prevents tumor necrosis factor-mediated inhibition of stress-related genes.
• Alternative EPO signaling modulates inflammation and promotes tissue homeostasis.
KeywordsARA290 Oxidative stress Heat shock Apoptosis TNFα Homeostasis Mesenchymal stem cells
The peptides ARA290 and ARA297 were kindly provided by Araim Pharmaceuticals, Inc. (Ossining, NY). This work was partially funded by the Shriners Hospitals for Children and grants from the National Institutes of Health (P41EB002503, R21AR056446). S. Bohr is a receipt of a Deutsche Forschungs Gemeinschaft (GZ:BO3468/2-1). S. J. Patel was supported by a Shriners Hospitals for Children postdoctoral fellowship.
Conflict of interest
M.B. and A.C. are officers of Araim Pharmaceuticals and currently hold stock in the company. All other authors state no conflict of interest.
- 3.Brines M, Grasso G, Fiordaliso F, Sfacteria A, Ghezzi P, Fratelli M, Latini R, Xie QW, Smart J, Su-Rick CJ et al (2004) Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci U S A 101:14907–14912PubMedCentralPubMedCrossRefGoogle Scholar
- 4.Brines M, Patel NS, Villa P, Brines C, Mennini T, De Paola M, Erbayraktar Z, Erbayraktar S, Sepodes B, Thiemermann C et al (2008) Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc Natl Acad Sci U S A 105:10925–10930PubMedCentralPubMedCrossRefGoogle Scholar
- 12.Bohr S, Patel SJ, Shen K, Vitalo AG, Brines M, Cerami A, Berthiaume F, Yarmush ML (2013) Alternative erythropoietin-mediated signaling prevents secondary microvascular thrombosis and inflammation within cutaneous burns. Proc Natl Acad Sci U S A 1214099110Google Scholar