Macrophages as novel target cells for erythropoietin

Abstract

BackgroundOur original demonstration of immunomodulatory effects of erythropoietin in multiple myeloma led us to the search for the cells in the immune system that are direct targets for erythropoietin. The finding that lymphocytes do not express erythropoietin receptors led to the hypothesis that other cells act as direct targets and thus mediate the effects of erythropoietin. The finding that erythropoietin has effects on dendritic cells thus led to the question of whether macrophages act as target cells for erythropoietin. Design and MethodsThe effects of erythropoietin on macrophages were investigated both in-vivo and in-vitro. The in-vivo studies were performed on splenic macrophages and inflammatory peritoneal macrophages, comparing recombinant human erythropoietin-treated and untreated mice, as well as transgenic mice over-expressing human erythropoietin (tg6) and their control wild-type counterparts. The in-vitro effects of erythropoietin on macrophage surface markers and function were investigated in murine bone marrow-derived macrophages treated with recombinant human erythropoietin. ResultsErythropoietin was found to have effects on macrophages in both the in-vivo and in-vitro experiments. In-vivo treatment led to increased numbers of splenic macrophages, and of the splenic macrophages expressing CD11b, CD80 and major histocompatibility complex class II. The peritoneal inflammatory macrophages obtained from erythropoietin-treated mice displayed increased expression of F4/80, CD11b, CD80 and major histocompatibility complex class II, and augmented phagocytic activity. The macrophages derived in-vitro from bone marrow cells expressed erythropoietin receptor transcripts, and in-vitro stimulation with erythropoietin activated multiple signaling pathways, including signal transducer and activator of transcription (STAT)1 and 5, mitogen-activated protein kinase, phosphatidylinositol 3-kinase and nuclear factor kappa B. In-vitro erythropoietin treatment of these cells up-regulated their surface expression of CD11b, F4/80 and CD80, enhanced their phagocytic activity and nitric oxide secretion, and also led to augmented interleukin 12 secretion and decreased interleukin 10 secretion in response to lipopolysaccharide. ConclusionsOur results show that macrophages are direct targets of erythropoietin and that erythropoietin treatment enhances the pro-inflammatory activity and function of these cells. These findings point to a multifunctional role of erythropoietin and its potential clinical applications as an immunomodulating agent.Key words: erythropoietin receptor, pro-inflammation, macrophages, signal transducer and activator of transcription (STAT).Citation: Lifshitz L, Tabak G, Gassmann M, Mittelman M, and Neumann D. Macrophages as novel target cells for erythropoietin. Haematologica 2010;95(11):1823-1831. doi:10.3324/haematol.2010 This is an open-access paper. Macrophages as novel target cells for erythropoietin

Erythropoietin Protects against Murine Cerebral Malaria through Actions on Host Cellular Immunity

“…The anti-inflammatory effects of EPO in ECM are highly compatible with that in disease conditions such as EAE, which involves excessive or dysregulated inflammatory responses (10)(11)(12)14). The immunosuppressive action of EPO might be exerted on DCs and macrophages, since these cells express remarkable amounts of EPOR-␤cR (14,40). In contrast, the expression of heterodimeric EPOR complexes is relatively low in CD4 ϩ T cells (14).…”

“…4A). Murine macrophages, as important effector cells, express considerable amounts of EPOR and CD131 and are therefore targets of EPO (14,40). EPO has been shown to downregulate the expression of inflammatory cytokines by macrophages in vitro.…”

Non-erythroid effects of erythropoietin

“…Although EPO was originally believed to be an erythroid-specific hematopoietic cytokine, for over a decade, a substantial body of scientific evidence has accumulated to demonstrate that the biological effects of EPO are not limited to the erythron (Figure 1). In this issue of the journal, Lifshitz and colleagues 1 report on their most recent contribution to this field of research by demonstrating that, within the hematopoietic system, EPO may exhibit modulatory effects on macrophage number and function. The authors examined in vivo effects of EPO on splenic macrophages and inflammatory peritoneal macrophages, as well as in vitro effects of EPO on bone marrow-derived macrophages in culture.…”

“…The last can be triggered by specialized receptors belonging to a subgroup of the tumor necrosis factor receptor superfamily called death receptors. 1 Fas, also termed tumor necrosis factor receptor superfamily 6 (TNFRSF 6), CD95 or Apo-1, is the prototypic member of the death receptor family. Its intracellular domain of 60 to 80 amino acid residues called the death domain allows homotypic interactions with a cytoplasmic death domain-containing protein named the Fasassociated death domain (FADD).…”

Immunotherapeutic effects of recombinant adenovirus encoding granulocyte–macrophage colony-stimulating factor in experimental pulmonary tuberculosis

“…High expression of F4/80 has been associated with the presence of inflammatory macrophages, overexpression of MHC II, CD80, CD11b and increased production of NO and IL-12 [24,25]. Similarly, F4/80 has been related to the early formation of granulomas induced by bacillus Calmette-Guérin (BCG) [26].…”