Abstract
Two distinct forms of the erythropoietin receptor (EPOR) mediate the cellular responses to erythropoietin (EPO) in different tissues. EPOR homodimers signal to promote the maturation of erythroid progenitor cells. In other cell types, including immune cells, EPOR and the ß-common receptor (CD131) form heteromers (the innate repair receptor; IRR), and exert tissue protective effects. We used dextran sulphate sodium (DSS) to induce colitis in C57BL/6 N mice. Once colitis was established, mice were treated with solvent, EPO or the selective IRR agonist cibinetide. We found that both cibinetide and EPO ameliorated the clinical course of experimental colitis in mice, resulting in improved weight gain and survival. Correspondingly, DSS-exposed mice treated with cibinetide or EPO displayed preserved tissue integrity due to reduced infiltration of myeloid cells and diminished production of pro-inflammatory disease mediators including cytokines, chemokines and nitric oxide synthase-2. Experiments using LPS-activated primary macrophages revealed that the anti-inflammatory effects of cibinetide were dependent on CD131 and JAK2 functionality and were mediated via inhibition of NF-κB subunit p65 activity. Cibinetide activation of the IRR exerts potent anti-inflammatory effects, especially within the myeloid population, reduces disease activity and mortality in mice. Cibinetide thus holds promise as novel disease-modifying therapeutic of inflammatory bowel disease.
Highlights
Erythropoietin (EPO) is a type I cytokine that fulfills dual functions
We questioned whether this effect depended on innate repair receptor (IRR) activation by determining whether the specific IRR agonist cibinetide improved dextran sulphate sodium (DSS)-colitis, where pathophysiology and tissue damage are centrally driven by nuclear factor (NF)-κB regulated pathways
The observation that in vivo cibinetide treatment dampens the ex vivo secretion of Ccl[2], Ccl[3], Cxcl[1] and Ccl[11] by FAC-sorted monocytes and macrophages further suggests that the recruitment of inflammatory cells to the colonic lamina propria is dampened by activation of the IRR of myeloid cells
Summary
Erythropoietin (EPO) is a type I cytokine that fulfills dual functions. In its classical endocrine role, EPO produced by the kidney acts as the key regulator of erythropoiesis via inhibition of erythroid progenitor cell apoptosis and stimulation of differentiation[1,2]. It has been shown that EPO ameliorates disease activity in experimental arthritis, encephalomyelitis and colitis in mice, suggesting that EPO exerts anti-inflammatory and tissue protective effects in autoimmune diseases[13,14,15,16]. These pleiotropic effects of EPO are transduced by two different receptor isoforms[3]. In vivo models of myocardial and hepatic ischemia/reperfusion injury have shown that EPO treatment protected from tissue damage via inhibition of NF-κB activation[10,22]. Cibinetide improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal small nerve fiber abundance
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