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

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  • Additional Information
    • Source:
      Publisher: Ferrata Storti Foundation Country of Publication: Italy NLM ID: 0417435 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1592-8721 (Electronic) Linking ISSN: 03906078 NLM ISO Abbreviation: Haematologica
    • Publication Information:
      Publication: 1999- : Pavia, Italy : Ferrata Storti Foundation
      Original Publication: Pavia [etc.]
    • Subject Terms:
      Signal Transduction*; Cytokine Receptor Common beta Subunit/*metabolism ; Erythroblasts/*metabolism ; Macrophages/*metabolism ; Polycythemia/*etiology ; Polycythemia/*metabolism ; Receptors, Erythropoietin/*metabolism; Animals ; Biomarkers ; Cell Count ; Cytokine Receptor Common beta Subunit/genetics ; Cytokines/metabolism ; Disease Models, Animal ; Erythroblasts/drug effects ; Erythropoietin/pharmacology ; Gene Expression Regulation/drug effects ; Gene Order ; Genes, Reporter ; Genetic Vectors ; Inflammation Mediators/metabolism ; Macrophages/drug effects ; Mice ; Mice, Transgenic ; Models, Biological ; Phenotype ; Polycythemia/pathology ; Receptors, Erythropoietin/genetics
    • 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 Jak2 V617F/+ allele with LysM -Cre allele which expresses in mature myeloid cells and some of the HSC/Ps ( LysM -Cre; Jak2 V617F/+ 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.
      (Copyright© 2018 Ferrata Storti Foundation.)
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    • Grant Information:
      R01 CA155091 United States CA NCI NIH HHS; R01 DK105014 United States DK NIDDK NIH HHS
    • Accession Number:
      0 (Biomarkers)
      0 (Cytokine Receptor Common beta Subunit)
      0 (Cytokines)
      0 (Inflammation Mediators)
      0 (Receptors, Erythropoietin)
      0 (innate repair receptor)
      11096-26-7 (Erythropoietin)
    • Publication Date:
      Date Created: 20171021 Date Completed: 20190724 Latest Revision: 20190724
    • Publication Date:
      20250114
    • Accession Number:
      PMC5777189
    • Accession Number:
      10.3324/haematol.2017.172775
    • Accession Number:
      29051279