Erythropoietin mediates tissue protection through an erythropoietin and common β-subunit heteroreceptor

Abstract

The cytokine erythropoietin (Epo) is tissue-protective in preclinical models of ischemic, traumatic, toxic, and inflammatory injuries. We have recently characterized Epo derivatives that do not bind to the Epo receptor (EpoR) yet are tissue-protective. For example, carbamylated Epo (CEpo) does not stimulate erythropoiesis, yet it prevents tissue injury in a wide variety of in vivo and in vitro models. These observations suggest that another receptor is responsible for the tissue-protective actions of Epo. Notably, prior investigation suggests that EpoR physically interacts with the common ␤ receptor (␤cR), the signal-transducing subunit shared by the granulocyte-macrophage colony stimulating factor, and the IL-3 and IL-5 receptors. However, because ␤cR knockout mice exhibit normal erythrocyte maturation, ␤cR is not required for erythropoiesis. We hypothesized that ␤cR in combination with the EpoR expressed by nonhematopoietic cells constitutes a tissueprotective receptor. In support of this hypothesis, membrane proteins prepared from rat brain, heart, liver, or kidney were greatly enriched in EpoR after passage over either Epo or CEpo columns but covalently bound in a complex with ␤cR. Further, antibodies against EpoR coimmunoprecipitated ␤cR from membranes prepared from neuronal-like P-19 cells that respond to Epo-induced tissue protection. Immunocytochemical studies of spinal cord neurons and cardiomyocytes protected by Epo demonstrated cellular colocalization of Epo ␤cR and EpoR. Finally, as predicted by the hypothesis, neither Epo nor CEpo was active in cardiomyocyte or spinal cord injury models performed in the ␤cR knockout mouse. These data support the concept that EpoR and ␤cR comprise a tissue-protective heteroreceptor.

Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen–glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures

“…Many studies suggest a role of EPOR in tissue protection (Bernaudin et al, 1999;Siren et al, 2001), but the receptor complex mediating EPO hematopoietic effects and EPO neuroprotective actions differs in the affinity for EPO and the associated proteins involved (Masuda et al, 1993). Moreover, CEPO does not seem to bind to the EPOR despite displaying neuroprotective actions (Leist et al, 2004), but Brines et al (2004) recently reported that using knock out (KO) mice for the βcR subunit the neuroprotective effects of both EPO and CEPO were abolished. In characterizing the EPO molecule, Campana et al (1998) showed the presence of a region in the EPO molecule, not within the EPOR binding site, which is associated with neuroprotective actions.…”

Revisiting the role of erythropoietin for treatment of ocular disorders

“…1 However, ample studies have evinced the presence of EPO protein and its receptors in extra-hematopoietic tissues including the retina tissue. 2,3 In adults, there is a wide distribution of EPO and EPO receptors (EPOR) reported on the human retinal tissue [4][5][6][7] and retinal pigment epithelium (RPE) 4 (Figure 1). According to Grimm et al, 8 EPOR expression was initially found to localize on the inner segments and synaptic terminals of the photoreceptors.…”

The neuroprotective and neurorescue effects of carbamylated erythropoietin Fc fusion protein (CEPO-Fc) in a rat model of Parkinson’s disease

“…The protective effects of EPO are mediated through a receptor complex consisting of the EPO-R and the common beta receptor (Brines et al, 2004(Brines et al, , 2005. The hematopoietic effects, on the other hand, are due to EPO binding to the (EPO-R/EPO-R) receptor, a dimer composed of two EPO receptor units.…”

“…Its hematopoietic effects are mediated by the binding of EPO to the (EPO-R/EPO-R) receptor, a dimer composed of two EPO receptor units. Its tissue-protective properties, on the other hand, are mediated by its binding to a heteroreceptor complex consisting of an EPO receptor monomer and the common beta receptor (Brines et al, 2004).…”