Erythropoietin, a multifaceted protein with innate and adaptive immune modulatory activity

Abstract

Erythropoietin (EPO) is a glycoprotein produced mainly by the adult kidney in response to hypoxia and is the crucial regulator of red blood cell production. EPO receptors (EPORs), however, are not confined to erythroid cells, but are expressed by many organs including the heart, brain, retina, pancreas, and kidney, where they mediate EPO-induced, erythropoiesis-independent, tissue-protective effects. Some of these tissues also produce and locally release small amounts of EPO in response to organ injury as a mechanism of self-repair. Growing evidence shows that EPO possesses also important immune-modulating effects. Monocytes can produce EPO, and autocrine EPO/EPOR signaling in these cells is crucial in maintaining immunologic self-tolerance. New data in mice and humans also indicate that EPO has a direct inhibitory effect on effector/memory T cells, while it promotes formation of regulatory T cells. This review examines the nonerythropoietic effects of EPO, with a special emphasis on its modulating activity on innate immune cells and T cells and on how it affects transplant outcomes.

Keywords: T cell biology; erythropoietin; immunobiology; immunosuppression/immune modulation; kidney transplantation/nephrology; translational research/science.

Figure 1.

Homodimer and heterodimer EPOR signaling in T cells and APCs. A) EPO signaling through homodimer EPOR induces SHIP-1 activation that, through a cross-talk mechanism, silences signaling downstream IL-2Rβ. Since conventional T cells (Tconv) rely on IL-2Rβ signaling for activation, EPO/EPOR interaction inhibits their proliferation. In regulatory T cells (Tregs), signaling downstream IL-2Rβ is silenced by constitutive phosphatases, while signaling downstream IL-2Rγ, important for their function, is unaffected by EPO. Modified from (34). B) Both T cells and APC express heterodimer EPOR. While its signaling has no known effect in T cells, its activation in APCs increases transcription and translation of TGFβ and uPA genes. Similar to homodimer receptor, it also activates PI3K, MAPK and STAT5 phosphorylation (7). Other signaling pathways initiated by heterodimer EPOR include inhibition of the binding activity of NF-κB family members. Affinity of homodimer EPOR for EPO is 1,000 folds higher than that of heterodimer (7).

Figure 2.. EPO directly inhibits Tconv.

EPO directly inhibits conventional T cell (Tconv) expansion and IFN-γ production by activating homodimer EPOR that cross-talks with IL-2 receptor to silence its downstream signaling. EPO/EPOR signaling also induces STAT5 phosphorylation, but its impact on Tconv function is unclear.

Figure 3.. EPO increases Treg induction by increasing active TGFβ production in APCs.

In antigen presenting cells (APCs), EPO signaling through the heterodimer EPOR increases TGFβ and uPA transcripts. Urokinase-type plasminogen activator (uPA) cleaves the latency associated peptide (LAP) from pro-TGFβ to activate it and promote conversion of naïve CD4⁺ T cells into functional regulatory T cells (iTregs). See Figure 1 for further details.