Dexamethasone targeted directly to macrophages induces macrophage niches that promote erythroid expansion

Falchi, Mario; Varricchio, Lilian; Martelli, Fabrizio; Masiello, Francesca; Federici, Giulia; Zingariello, Maria; Girelli, Gabriella; Whitsett, Carolyn; Petricoin, Emanuel F.; Moestrup, Søren K.; Zeuner, Ann; Migliaccio, Anna Rita

doi:10.3324/haematol.2014.114405

Cited by 46 publications

(48 citation statements)

References 38 publications

(39 reference statements)

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“…Activation of VCAM-1 in both ECs and in macrophages by increased levels of glucocorticoids was found to be part of the E-stress response. 53,54 Further, VCAM-1 appears to be a target for hypoxia-inducible factor 1-a in ECs playing an essential role in supporting erythropoiesis, 55 because it impairs erythroid maturation. The increased reactive oxygen species occurring post-stress could also affect VCAM-1 activation in macrophages, as it occurs in ECs.…”

Section: Discussionmentioning

confidence: 99%

The macrophage contribution to stress erythropoiesis: when less is enough

Ulyanova

Phelps

Papayannopoulou

2016

Blood

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• Significant expansion only of native splenic macrophages that are F4/80 1 /Cd11b lo occurs in both post-Epo and post-hemolysis-induced stress.• VCAM-1 2/2 mice, like Spi-C 2/2 , mice have significantly decreased macrophages but did not have a compromised E-stress response.Although the importance of native bone marrow and spleen macrophages in enhancing baseline and stress erythropoiesis has been emphasized over several decades, their kinetic and phenotypic changes during a variety of stress responses have been unclear. Furthermore, whether monocyte-derived recruited macrophages can functionally substitute for inadequate or functionally impaired native macrophages has been controversial and seem to be not only tissue-but also stress-type dependent. To provide further insight into these issues, we made detailed observations at baseline and post-erythroid stress (E-stress) in 2 mouse models with genetically depressed macrophage numbers and compared them to their controls. We documented that, irrespective of the stressinduced (hemolytic or post-erythropoietin [Epo]) treatment, only native CD11b lo splenic macrophages expand dramatically post-stress in normal mice without significant changes in the monocyte-derived CD11b hi subset. The latter remained a minority and did not change post-stress in 2 genetic models lacking either Spi-C or VCAM-1 with impaired native macrophage proliferative expansion. Although CD11b lo macrophages in these mice were one-fifth of normal at their peak response, surprisingly, their erythroid response was not compromised and was similar to controls. Thus, despite the prior emphasis on numerical macrophage reliance to provide functional rescue from E-stress, our data highlight the importance of previously described non-macrophage-dependent pathways activated under certain stress conditions to compensate for low macrophage numbers. (Blood. 2016;128(13):1756-1765

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Section: Discussionmentioning

confidence: 99%

The macrophage contribution to stress erythropoiesis: when less is enough

Ulyanova

Phelps

Papayannopoulou

2016

Blood

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“…At day 10, cells were analyzed by flow cytometry with CD36 and CD235a to assess maturation [27,29] and subjected to further analyses.…”

Section: Methodsmentioning

confidence: 99%

The Calreticulin control of human stress erythropoiesis is impaired by JAK2V617F in polycythemia vera

Falchi

Varricchio

Martelli

et al. 2017

Experimental Hematology

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Calreticulin (CALR) is a Ca2+-binding protein that shuttles among cellular compartments with proteins bound to its N/P domains. The knowledge that activation of the human erythropoietin receptor induces Ca2+ fluxes prompted us to investigate the role of CALR in human erythropoiesis. As shown by Western blot analysis, erythroblasts generated in vitro from normal sources and JAK2V617F polycythemia vera (PV) patients expressed robust levels of CALR. However, Ca2+ regulated CALR conformation only in normal cells. Normal erythroblasts expressed mostly the N-terminal domain of CALR (N-CALR) on their cell surface (as shown by flow cytometry) and C-terminal domain (C-CALR) in their cytoplasm (as shown by confocal microscopy) and expression of both epitopes decreased with maturation. In the proerythroblast (proEry) cytoplasm, C-CALR was associated with the glucocorticoid receptor (GR), which initiated the stress response. In these cells, Ca2+ deprivation and inhibition of nuclear export increased GR nuclear localization while decreasing cytoplasmic detection of C-CALR and C-CALR/GR association and proliferation in response to the GR agonist dexamethasone (Dex). C-CALR/GR association and Dex responsiveness were instead increased by Ca2+ and erythropoietin. In contrast, JAK2V617F proErys expressed normal cell-surface levels of N-CALR but barely detectable cytoplasmic levels of C-CALR. These cells contained GR mainly in the nucleus and were Dex unresponsive. Ruxolitinib rescued cytoplasmic detection of C-CALR, C-CALR/GR association, and Dex responsiveness in JAK2V617F proErys and its effects were antagonized by nuclear export and Ca2+ flux inhibitors. These results indicates that Ca2+-induced conformational changes of CALR regulate nuclear export of GR in normal erythroblasts and that JAK2V617F deregulates this function in PV.

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“…100 Additional factors that might contribute to SE are the RNA-binding protein ZFP36L2, 101 the Notch receptor 2, 102 the anti-inflammatory polymeric immunoglobulin A1 (pIgA1) 103 and dexamethasone. 104 In particular, dexamethasone, in addition to inducing proliferation of proerythroblasts, 105 stimulates expansion of these cells indirectly by supporting the activity of macrophages. 105 …”

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confidence: 99%

“…104 In particular, dexamethasone, in addition to inducing proliferation of proerythroblasts, 105 stimulates expansion of these cells indirectly by supporting the activity of macrophages. 105 …”

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confidence: 99%

-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

2015

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b-thalassemias are monogenic disorders characterized by defective synthesis of the b-globin chain, one of the major components of adult hemoglobin. A large number of mutations in the b-globin gene or its regulatory elements have been associated with b-thalassemias. Due to the complexity of the regulation of the b-globin gene and the role of red cells in many physiological processes, patients can manifest a large spectrum of phenotypes, and clinical requirements vary from patient to patient. It is important to consider the major differences in the light of potential novel therapeutics. This review summarizes the main discoveries and mechanisms associated with the synthesis of b-globin and abnormal erythropoiesis, as well as current and novel therapies. ABSTRACTThe complex phenotype of b-thalassemias b-thalassemias are monogenic disorders characterized by reduced or no synthesis of the b-globin chain, one of the major components of adult hemoglobin (HbA). Several hundred mutations in the b-globin gene or regulatory elements have been associated with b-thalassemias.

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Dexamethasone targeted directly to macrophages induces macrophage niches that promote erythroid expansion

Cited by 46 publications

References 38 publications

The macrophage contribution to stress erythropoiesis: when less is enough

The macrophage contribution to stress erythropoiesis: when less is enough

The Calreticulin control of human stress erythropoiesis is impaired by JAK2V617F in polycythemia vera

-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

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