Erythropoietin Contrastingly Affects Bacterial Infection and Experimental Colitis by Inhibiting Nuclear Factor-κB-Inducible Immune Pathways

Abstract

SummaryErythropoietin (EPO) is the principal cytokine regulating erythropoiesis through its receptor, EPOR. Interestingly, EPORs are also found on immune cells with incompletely understood functions. Here, we show that EPO inhibits the induction of proinflammatory genes including tumor necrosis factor (TNF)-α and inducible nitric oxide (NO) synthase in activated macrophages, which is mechanistically attributable to blockage of nuclear factor (NF)-κB p65 activation by EPO. Accordingly, in systemic Salmonella infection, treatment of mice with EPO results in reduced survival and impaired pathogen clearance because of diminished formation of anti-microbial effector molecules such as TNF-α and NO. However, neutralization of endogenous EPO or genetic ablation of Epor promotes Salmonella elimination. In contrast, in chemically induced colitis, EPO-EPOR interaction decreases the production of NF-κB-inducible immune mediators, thus limiting tissue damage and ameliorating disease severity. These immune-modulatory effects of EPO may be of therapeutic relevance in infectious and inflammatory diseases.

Hepcidin Is Regulated during Blood-Stage Malaria and Plays a Protective Role in Malaria Infection

“…A negative correlation was found between the levels of hepcidin mRNA and serum EPO. A recent study has demonstrated that EPO inhibits the induction of IL-6 in macrophages after LPS treatment or in spleens of mice after Salmonella infection (37). The action mediated by EPO is attributable to blockage of NF-kB p65 activation.…”

Immunosuppressive Effects of Erythropoietin on Human Alloreactive T Cells

“…5 Analogously, finding that EPO inhibits T-cell expansion in response to polyclonal stimuli and prevents Th1 differentiation of naïve CD4 + T cells may partially explain previous data showing that EPO downregulates proinflammatory immune effector pathways in response to chemical tissue damage, LPS stimulation, and Salmonella infection. 6,[30][31][32] In patients with rheumatoid arthritis, treatment with recombinant EPO not only resulted in amelioration of anemia but also improved disease activity. 33 Intriguingly, EPO has been associated with adverse outcomes of tumor progression and impaired survival in a series of clinical trials, 34,35 a finding that might be explained, at least in part, by EPO-induced inhibition of antitumor T-cell immunity.…”

The Receptor That Tames the Innate Immune Response

“…A primary characteristic of this program is expression of a specific tissue-protective receptor (TPR) (stage 3) and, after a significant time delay (hours) (7), expression of its ligand, which is now known to be erythropoietin (EPO) (stage 4). EPO signals through the TPR to inhibit proinflammatory cytokine production (8), inhibit macrophage activity (9) and delimit the volume of injury by counteracting apoptosis (10) (stage 5). The TPR also acts to recruit vascularand tissue-specific stem cells (11) and enhances tissue repair (12) (stage 6).…”

“…A variety of tissues that have been examined for expression of βCR and EPOR, including the central ( Figure 4A [35]) and peripheral (43) nervous systems, retina (44), heart (45), kidney (46), muscle (47) and the endothelium (48). Additionally, components of the immune system that are resident or migrate to regions of injury also highly express subunits for the TPR as, for example, specific subsets of macrophages (9).…”

“…In the central nervous system, therefore, tissue-protective molecules can affect biological function in the normal organism. Another cell type that expresses both EPOR and βCR at baseline are tissue macrophages (9). These cells are therefore "primed" for activation by tissue-protective ligands and may explain the ability of EPO to reduce the level of proinflammatory cytokines produced by macrophages, thus reducing the degree of further tissue damage.…”