The pleiotropic effects of erythropoietin in infection and inflammation

Abstract

Erythropoietin (EPO) is a multi-functional cytokine, which exerts erythropoietic effects but also carries anti-apoptotic and immune-modulatory activities upon binding to two distinct receptors which are expressed on erythroid, parenchymal and immune cells, respectively. Whereas EPO ameliorates hemolytic anemia in malaria or trypanosomiasis and improves the course of autoimmune diseases such as inflammatory bowel disease or autoimmune encephalomyelitis, it deleteriously inhibits macrophage functions in Salmonella infection in animal models. Thus, the specific modulation of extra-erythropoietic EPO activity forms an attractive therapeutic target in infection and inflammation.

Fig. 1

Immune-modulatory effects of EPO: Erythropoietin (EPO) is secreted by peritubular fibroblasts in response to activation of hypoxia inducible factor (HIF)-1α, while nitric oxide (NO) and other pro-inflammatory mediators produced in the presence of infectious agents inhibit renal EPO expression. In erythroid cells, EPO inhibits the elimination of erythroid progenitors by FasL-Fas-induced apoptosis following activation of signal transducer and activator of transcription (STAT)-5. In immune cells, a heterodimeric receptor consisting of an EPO receptor subunit (EPOR) and a β common receptor (βcR) subunit is activated upon binding of EPO. As a consequence, EPO impairs the generation of reactive oxygen species (ROS) by neutrophils and of nuclear factor (NF)-κB-inducible macrophage effectors such as tumor necrosis factor (TNF)-α and NO. Apparently, EPO also converts the functionality of T helper (Th)-1 or Th-17 cells, respectively, to an immune-tolerant phenotype. Whereas EPO stimulates antibody production by plasma cells, its putative effects on other types of immune cells remain elusive. Green arrows indicate stimulatory pathways, red arrows indicate inhibitory pathways, gray arrows indicate putative interactions. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Alternative EPO-induced signaling in immune cells: Macrophage effector functions are regulated by the integration of a broad range of signaling pathways. While toll-like receptors (TLRs) activated via pathogen-derived ligands such as lipopolysaccharide (LPS) and macrophage-activating lipopeptide (MALP)-2 initiate signal transduction via myeloid differentiation primary response gene (MyD)-88 and TNF receptor associated factor (TRAF)-6, binding of (TNF)-α to its receptor (TNFR)-1 activates TRAF-2. Subsequently, transforming growth factor-β-activated kinase (TAK)-1 activates NF-κB via IκB kinase (IKK) and inhibitor of κB (IκB)-α. Binding of EPO to the EPOR-βcR heteroreceptor activates Janus kinase (JAK)-2. JAK-2 is linked to several other pathways including STAT-5 and the RAS-MEK-ERK-MAPK cascade. Phosphoinositide 3-kinase (PI3K) is known to inhibit MAPK, while EPO inhibits activator protein (AP)-1 by a yet unidentified mechanism. While NO production is reduced by EPO, NO in turn impairs EPOR expression. HIF and NF-κB transcription factors show reciprocal positive interactions, yet have diverse effects on EPO transcription since HIF stimulates, while NF-κB inhibits EPO expression. Green arrows indicate stimulatory pathways, red arrows indicate inhibitory pathways, gray arrows indicate putative interactions. Abbreviations: Ras - rat sarcoma; MEK - mitogen-activated protein kinase kinase; MAPK - mitogen-activated protein kinase; ERK - extracellular signal-regulated kinase. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

The EPO-immunity regulatory network affects host–pathogen interaction: Microbes induce host response pathways for example via activation of Toll-like receptors (TLRs), thereby leading to stimulation of the NF-κB pathway and subsequent transcription of genes such as tumor necrosis factor (TNF)-α or inducible nitric oxide (NO) synthase (iNOS) resulting in formation of the toxic radical NO, needed for effective anti-microbial immune responses. In contrast, after binding to its specific cell surface receptor, EPO inhibits these pro-inflammatory immune effector pathways. Thus, to ensure an effective pro-inflammatory immune response during infection, immune-derived molecules such as TNF-α and NO reduce the anti-inflammatory activity of EPO by down-regulating expression of its cell surface receptor (EPOR) and by directly inhibiting EPO formation in the kidney. As a consequence, anemia develops which is due to reduced EPO availability and retention of iron within macrophages mostly based on the action of the acute phase protein hepcidin, whose expression is negatively controlled by EPO. Thus, by these pathways, the availability of oxygen and iron for rapidly growing tissues and/or extracellular microbes is reduced which may be part of the innate immune response, although the access of intracellular pathogens to iron may be contrastingly affected. Oppositely, anemia and hypoxia stimulate EPO formation via activation of hypoxia inducible factor (HIF) in the kidney but maybe also in other cells including macrophages. EPO down-regulates the pro-inflammatory immune response, thereby also reducing the anti-proliferative effects of this cytokine on erythroid progenitor cells. Furthermore, EPO inhibits hepcidin formation, thus enabling mobilization of iron from macrophage stores for erythropoietic use. These events lead to down-scaling of inflammation and correction of anemia after the infection has been cleared by anti-microbial effector pathways. Green arrows indicate stimulatory pathways, red arrows indicate inhibitory pathways. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)