Erythropoietin Signaling Increases Choroidal Macrophages and Cytokine Expression, and Exacerbates Choroidal Neovascularization

Bretz, Colin A.; Divoký, Vladimír; Prchal, Josef T.; Kunz, Eric; Simmons, Aaron B.; Wang, Haibo; Hartnett, M. Elizabeth

doi:10.1038/s41598-018-20520-z

Cited by 24 publications

(32 citation statements)

References 49 publications

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“…EPO can facilitate CCL2 production by Kupffer cells and promote the recruitment of monocytes to injured liver 29 . Similarly, increased levels of EPO can recruit more macrophages to laser-injured choroids 30 . This may be related to EPOinduced anti-apoptosis and proliferation effects after injury.…”

Section: Innate Immune System Macrophagementioning

confidence: 99%

Erythropoietin and its derivatives: from tissue protection to immune regulation

et al. 2020

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Erythropoietin (EPO) is an evolutionarily conserved hormone well documented for its erythropoietic role via binding the homodimeric EPO receptor (EPOR) 2. In past decades, evidence has proved that EPO acts far beyond erythropoiesis. By binding the tissue-protective receptor (TPR), EPO suppresses proinflammatory cytokines, protects cells from apoptosis and promotes wound healing. Very recently, new data revealed that TPR is widely expressed on a variety of immune cells, and EPO could directly modulate their activation, differentiation and function. Notably, nonerythropoietic EPO derivatives, which mimic the structure of helix B within EPO, specifically bind TPR and show great potency in tissue protection and immune regulation. These small peptides prevent the cardiovascular side effects of EPO and are promising as clinical drugs. This review briefly introduces the receptors and tissue-protective effects of EPO and its derivatives and highlights their immunomodulatory functions and application prospects.

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Section: Innate Immune System Macrophagementioning

confidence: 99%

Erythropoietin and its derivatives: from tissue protection to immune regulation

et al. 2020

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“…S2 ), which could be due to the dynamic expression patterns of cytokines during the 7 days following CNV induction. 23 At day 1 post-CNV, IL-8 protein levels were decreased by fursultiamine ( Supplementary Fig. S3 A).…”

Section: Resultsmentioning

confidence: 95%

Fursultiamine Alleviates Choroidal Neovascularization by Suppressing Inflammation and Metabolic Reprogramming

Yeon

Kim

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Purpose To assess the therapeutic effects of fursultiamine on choroidal neovascularization (CNV) through its modulation of inflammation and metabolic reprogramming in the retinal pigment epithelium (RPE). Methods The anti-angiogenic effects of fursultiamine were assessed by measuring vascular leakage and CNV lesion size in the laser-induced CNV mouse model. Inflammatory responses were evaluated by quantitative polymerase chain reaction, western blot, and ELISA in both CNV eye tissues and in vitro cell cultures using ARPE-19 cells or primary human RPE (hRPE) cells under lipopolysaccharide (LPS) treatment or hypoxia. Mitochondrial respiration was assessed by measuring oxygen consumption in ARPE-19 cells treated with LPS with or without fursultiamine, and lactate production was measured in ARPE-19 cells subjected to hypoxia with or without fursultiamine. Results In laser-induced CNV, fursultiamine significantly decreased vascular leakage and lesion size, as well as the numbers of both choroidal and retinal inflammatory cytokines, including IL-1β, IL-6, IL-8, and TNF-α. In LPS-treated ARPE-19 cells, fursultiamine decreased proinflammatory cytokine secretion and nuclear factor kappa B phosphorylation. Furthermore, fursultiamine suppressed LPS-induced upregulation of IL-6, IL-8, and monocyte chemoattractant protein-1 in a dose-dependent and time-dependent manner in primary hRPE cells. Interestingly, fursultiamine significantly enhanced mitochondrial respiration in the LPS-treated ARPE-19 cells. Additionally, fursultiamine attenuated hypoxia-induced aberrations, including lactate production and inhibitory phosphorylation of pyruvate dehydrogenase. Furthermore, fursultiamine attenuated hypoxia-induced VEGF secretion and mitochondrial fission in primary hRPE cells that were replicated in ARPE-19 cells. Conclusions Our findings show that fursultiamine is a viable putative therapeutic for neovascular age-related macular degeneration by modulating the inflammatory response and metabolic reprogramming by enhancing mitochondrial respiration in the RPE.

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“…Finally, as high EPO-exposure has been linked to changes in macrophage numbers [41][42][43][44][45][46][47][48] we analyzed the contribution of control and EPO-exposed HSPCs to the myeloid lineage in more detail, but could not detect changes in the percentage of the different myeloid subsets produced ( Supplementary Figure 6a-c).…”

Section: Epomentioning

confidence: 99%

Erythropoietin directly remodels the clonal composition of murine hematopoietic multipotent progenitor cells

Eisele

Cosgrove

Magniez

et al. 2020

Preprint

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The cytokine erythropoietin (EPO) is a potent inducer of erythrocyte development and one of the most prescribed biopharmaceuticals. The action of EPO on erythroid progenitor cells is well established, but its action on hematopoietic stem cells (HSCs) is still debated. Here, using cellular barcoding, we traced the differentiation of hundreds of single HSCs, after in vitro EPO exposure and transplantation, in five different hematopoietic cell lineages, and observed the occurrence of high-output Myeloid-Erythroid-megaKaryocyte (MEK)-biased and Myeloid-B-cell-Dendritic cell (MBDC)-biased clones. ScRNAseq analysis of in vitro EPO-exposed HSCs revealed upregulation of erythroid associated genes in a subset of HSCs. Collectively, as well as demonstrating a direct effect of EPO on HSCs, our results suggest an EPO-mediated induction of MEK-bias in multi-outcome HSCs, and that this change in output is functionally compensated by MBDC-biased HSCs.

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Erythropoietin Signaling Increases Choroidal Macrophages and Cytokine Expression, and Exacerbates Choroidal Neovascularization

Cited by 24 publications

References 49 publications

Erythropoietin and its derivatives: from tissue protection to immune regulation

Erythropoietin and its derivatives: from tissue protection to immune regulation

Fursultiamine Alleviates Choroidal Neovascularization by Suppressing Inflammation and Metabolic Reprogramming

Erythropoietin directly remodels the clonal composition of murine hematopoietic multipotent progenitor cells

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