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Expansion of EPOR-negative macrophages besides erythroblasts by elevated EPOR signaling in erythrocytosis mouse models.

ABSTRACT: Activated erythropoietin (EPO) receptor (EPOR) signaling causes erythrocytosis. The important role of macrophages for the erythroid expansion and differentiation process has been reported, both in baseline and stress erythropoiesis. However, the significance of EPOR signaling for regulation of macrophages contributing to erythropoiesis has not been fully understood. Here we show that EPOR signaling activation quickly expands both erythrocytes and macrophages in vivo in mouse models of primary and secondary erythrocytosis. To mimic the chimeric condition and expansion of the disease clone in the polycythemia vera patients, we combined Cre-inducible Jak2V617F/+ allele with LysM-Cre allele which expresses in mature myeloid cells and some of the HSC/Ps (LysM-Cre;Jak2V617F/+ mice). We also generated inducible EPO-mediated secondary erythrocytosis models using Alb-Cre, Rosa26-loxP-stop-loxP-rtTA, and doxycycline inducible EPAS1-double point mutant (DPM) alleles (Alb-Cre;DPM mice). Both models developed a similar degree of erythrocytosis. Macrophages were also increased in both models without increase of major inflammatory cytokines and chemokines. EPO administration also quickly induced these macrophages in wild-type mice before observable erythrocytosis. These findings suggest that EPOR signaling activation could induce not only erythroid cell expansion, but also macrophages. Surprisingly, an in vivo genetic approach indicated that most of those macrophages do not express EPOR, but erythroid cells and macrophages contacted tightly with each other. Given the importance of the central macrophages as a niche for erythropoiesis, further elucidation of the EPOR signaling mediated-regulatory mechanisms underlying macrophage induction might reveal a potential therapeutic target for erythrocytosis.

SUBMITTER: Wang J

PROVIDER: S-EPMC5777189 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Expansion of EPOR-negative macrophages besides erythroblasts by elevated EPOR signaling in erythrocytosis mouse models.

Wang Jieyu J Hayashi Yoshihiro Y Yokota Asumi A Xu Zefeng Z Zhang Yue Y Huang Rui R Yan Xiaomei X Liu Hongyun H Ma Liping L Azam Mohammad M Bridges James P JP Cancelas Jose A JA Kalfa Theodosia A TA An Xiuli X Xiao Zhijian Z Huang Gang G

Haematologica 20171019 1

Activated erythropoietin (EPO) receptor (EPOR) signaling causes erythrocytosis. The important role of macrophages for the erythroid expansion and differentiation process has been reported, both in baseline and stress erythropoiesis. However, the significance of EPOR signaling for regulation of macrophages contributing to erythropoiesis has not been fully understood. Here we show that EPOR signaling activation quickly expands both erythrocytes and macrophages <i>in vivo</i> in mouse models of pri ...[more]

PMID: 29051279

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Project description:Erythrocytosis is the most common dose limiting adverse effect of testosterone therapy but the mechanisms of testosterone mediated erythropoiesis remain unclear. In this study we examine risk factors for erythrocytosis associated with testosterone therapy.A retrospective review was performed of 179 hypogonadal men on testosterone therapy at a single andrology clinic. Demographic data, testosterone therapy formulation and duration of treatment, and 5?-reductase inhibitor use were assessed. Serum dihydrotestosterone, total testosterone, free testosterone, follicle-stimulating hormone, luteinizing hormone, hematocrit and lipid levels were extracted, and changes during treatment were determined. Spearman's rank correlation was used to identify relationships between change in hematocrit and study variables.Of 179 patients 49 (27%) experienced a 10% or greater change in hematocrit and erythrocytosis (hematocrit 50% or greater) developed in 36 (20.1%) at a median followup of 7 months. Topical gels were used by 41.3% of patients, injectable testosterone by 52.5% and subcutaneous pellets by 6.1%. More men who experienced a change in hematocrit of 10% or greater used injectable testosterone than men with a change in hematocrit of less than 10% (65% vs 48%, p=0.035), and were less likely to be on a 5?-reductase inhibitor (2% vs 15%, p=0.017). Men with a change in hematocrit of 10% or greater had higher posttreatment dihydrotestosterone levels (605.0 vs 436.0 ng/dl, p=0.017) and lower luteinizing hormone and follicle-stimulating hormone levels than men with a change in hematocrit of less than 10%. Spearman's rank correlations yielded relationships between change in hematocrit and posttreatment dihydrotestosterone ?=0.258, p=0.001) and total testosterone (?=0.171, p=0.023).Dihydrotestosterone may have a role in testosterone therapy related erythrocytosis and monitoring dihydrotestosterone levels during testosterone therapy should be considered. In men in whom erythrocytosis develops, 5?-reductase inhibitors may be therapeutic.

Dataset Information

Expansion of EPOR-negative macrophages besides erythroblasts by elevated EPOR signaling in erythrocytosis mouse models.

Publications

Expansion of EPOR-negative macrophages besides erythroblasts by elevated EPOR signaling in erythrocytosis mouse models.

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