Macrophage development from HSCs requires PU.1-coordinated microRNA expression

Ghani, Saeed; Riemke, Pia; Schönheit, Jörg; Lenze, Dido; Stumm, Jürgen; Hoogenkamp, Maarten; Lagendijk, Anne Karine; Heinz, Sven; Bonifer, Constanze; Bakkers, Jeroen; Abdelilah‐Seyfried, Salim; Hummel, Michael; Rosenbauer, Frank

doi:10.1182/blood-2011-02-335141

Cited by 109 publications

(109 citation statements)

References 54 publications

(86 reference statements)

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“…26,27 However, the functional role of miR-342-5p was unclear. We have shown that increased miR-342-5p expression sensitizes macrophages to proinflammatory stimulation by regulating Nos2.…”

Section: Discussionmentioning

confidence: 99%

The microRNA-342-5p Fosters Inflammatory Macrophage Activation Through an Akt1- and microRNA-155 –Dependent Pathway During Atherosclerosis

et al. 2013

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Background-Atherosclerosis is a chronic inflammatory vascular disease driven by the subendothelial accumulation of macrophages. The mechanism regulating the inflammatory response in macrophages during atherogenesis remains unclear. Because microRNAs (miRNAs) play a crucial role in cellular signaling by posttranscriptional regulation of gene expression, we studied the miRNA expression profiles during the progression of atherosclerosis. Methods and Results-Using an miRNA real-time polymerase chain reaction array, we found that macrophage-derived miR-342-5p and miR-155 are selectively upregulated in early atherosclerotic lesions in Apoe −/− mice. miR-342-5p directly targets Akt1 through its 3ʹ-untranslated region. Akt1 suppression by miR-342-5p induces proinflammatory mediators such as Nos2 and II6 in macrophages via the upregulation of miR-155. The local application of an miR-342-5p antagomir inhibits the development of atherosclerosis in partially ligated carotid arteries. In atherosclerotic lesions, the miR-342-5p antagomir upregulated Akt1 expression and suppressed the expression of miR-155 and Nos2. This reduced Nos2 expression was associated with a diminished generation of nitrotyrosine in the plaques. Furthermore, systemic treatment with an inhibitor of miR-342-5p reduced the progression of atherosclerosis in the aorta of Apoe −/− mice. miR-223, miR-155, and miR-146a govern the proinflamma tory activation of macrophages by regulating the nuclear factor-κB signaling pathway. 9,15 The atherogenic stimulation of monocytes and macrophages by oxidized low-density lipoprotein also alters the miRNA expression profile, including the expression of miR-155 and miR-146a; this, in turn, affects lipid uptake and inflammatory cytokine secretion. 16 Moreover, inhibition of miR-33 causes an increase in reverse cholesterol transport, thereby reducing atherosclerosis and inflammatory gene expression. Conclusions-Macrophage-derived miR-342-5p 17Thus, miRNAs may be crucial for the regulation of inflammatory and lipid-handling functions in lesional macrophages. However, the miRNAs that control the inflammatory response during atherosclerosis have not been identified.In this study, we generated stage-specific miRNA expression profiles in atherosclerotic lesions from Apoe −/− mice. During early atherosclerosis, the most prominently upregulated miRNA was miR-342-5p, which is expressed in lesional macrophages. On proinflammatory activation in macrophages in vitro, miR-342-5p promoted Nos2 expression in an miR-155-dependent manner by targeting Akt1, an inhibitor of miR-155 expression. Accordingly, the inhibition of miR-342-5p reduced atherosclerotic lesion formation and suppressed Akt1-dependent Nos2 expression in lesional macrophages. Taken together, these data demonstrate a crucial role for miR-342-5p in the early inflammatory response in lesional macrophages. Methods Animal ModelsApoe −/− mice (age, 6-8 weeks; The Jackson Laboratory, Bar Harbor, ME) were fed a high-cholesterol diet (HCD; Altromin, Germany) comprising 21% crude ...

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“…26,27 However, the functional role of miR-342-5p was unclear. We have shown that increased miR-342-5p expression sensitizes macrophages to proinflammatory stimulation by regulating Nos2.…”

Section: Discussionmentioning

confidence: 99%

The microRNA-342-5p Fosters Inflammatory Macrophage Activation Through an Akt1- and microRNA-155 –Dependent Pathway During Atherosclerosis

et al. 2013

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“…In early T-cell stages, PU.1 drives expression of cytokine receptors such as Il7r and Flt3, and of genes that are important for cell communication (Turkistany and DeKoter, 2011). However, it is also required for the development and function of other cell types, including hematopoietic stem cells (Iwasaki et al, 2005), multipotent progenitors (Wontakal et al, 2011), myeloid cells (Ghani et al, 2011) and B cells (Houston et al, 2007). Forced overexpression of PU.1 can divert early T cells to a myeloid lineage (Anderson et al, 2002;Dionne et al, 2005;Lefebvre et al, 2005;Laiosa et al, 2006b).…”

Section: Introductionmentioning

confidence: 99%

Architecture of a lymphomyeloid developmental switch controlled by PU.1, Notch and Gata3

2013

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Hematopoiesis is a classic system with which to study developmental potentials and to investigate gene regulatory networks that control choices among alternate lineages. T-cell progenitors seeding the thymus retain several lineage potentials. The transcription factor PU.1 is involved in the decision to become a T cell or a myeloid cell, and the developmental outcome of expressing PU.1 is dependent on exposure to Notch signaling. PU.1-expressing T-cell progenitors without Notch signaling often adopt a myeloid program, whereas those exposed to Notch signals remain in a T-lineage pathway. Here, we show that Notch signaling does not alter PU.1 transcriptional activity by degradation/alteration of PU.1 protein. Instead, Notch signaling protects against the downregulation of T-cell factors so that a T-cell transcriptional network is maintained. Using an early T-cell line, we describe two branches of this network. The first involves inhibition of E-proteins by PU.1 and the resulting inhibition of Notch signaling target genes. Effects of E-protein inhibition can be reversed by exposure to Notch signaling. The second network is dependent on the ability of PU.1 to inhibit important T-cell transcription factor genes such as Myb, Tcf7 and Gata3 in the absence of Notch signaling. We show that maintenance of Gata3 protein levels by Myb and Notch signaling is linked to the ability to retain T-cell identity in response to PU.1.

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“…[30][31][32] miR146a is a modulator of innate and adaptive immunity, is involved in tumor progression and in hematopoiesis, and is required for stem/progenitor cell differentiation into monocytes/macrophages. [33][34][35][36] In malignant hematopoiesis, miR146a is involved in the pathogenesis of myelodysplastic syn- November 10, 2014 Manuscript accepted on May 28, 2015.…”

Section: Introductionmentioning

confidence: 99%

“…36 Under chronic, mild hypoxia, hematopoietic progenitor cells undergo a switch from the predominant HIF-1α expression and activation in undifferentiated CD34 + cells to the prevalent HIF-2α expression in differentiating monocytic precursors. This observation is in line with recent studies showing a key role of HIF-1α in maintaining the stemness of normal hematopoietic stem cells: in fact, in HIF-1α -/-mice hematopoietic stem cell numbers decrease during stress in association with a loss of quiescence.…”

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confidence: 99%

Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells: impact on response to chemotherapy

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o ndromes for its deletion on chromosome 5 37 and in the progression of chronic myeloid leukemia. 38 We previously identified the molecular mechanism that regulates the level of CXCR4 protein expression by miR146a targeting 29 (miR-146a/CXCR4) during monocytopoiesis. 39 We also reported that in acute monocytic leukemia (AML-M5), a high CXCR4 protein level is associated with low/absent miR-146a expression. 39 We then showed that enforced miR-146a expression in leukemic cells decreases the level of CXCR4 protein and improves the sensitivity of these cells to drugs. 39CXCR4 is a target gene of HIF-1α and a post-transcriptional target of miR-146a, 9,39 in monocytic cells, known to originate from a common myeloid precursor in the bone marrow giving rise to tissue macrophages and dendritic cells 40 and subject to very different oxygen (O 2 ) levels. 41In this study, we investigated the impact of chronic hypoxia on the miR-146a/CXCR4 regulatory axis during monocytopoiesis and in monocytic leukemic cells. The levels of hypoxia studied were mild (5% O 2 ), such as that present in the sinusoidal cavity of bone marrow, and more severe (1% O 2 ), such as that in hypoxic niches in bone marrow.Altogether, our data demonstrated how the differential expression of HIF-1α and HIF-2α is mediated by O 2 level (mild or severe) and down-regulates CXCR4 expression through a post-transcriptional mechanism mediated by up-regulation of miR-146a in normal monocytic cells and in monocytic leukemia cell lines, expressing a moderate level of CXCR4. However, this mechanism is dysregulated in primary AML-M5 blast cells that fail to decrease CXCR4 expression significantly in response to hypoxia. This dysregulation helps to explain why leukemic blasts express high CXCR4 levels, even in hypoxic conditions, and how they are protected from anti-leukemic drugs through CXCR4 activation mediated by SDF-1α secreted in the hypoxic bone marrow microenvironment. MethodsAdditional information is provided in the Online Supplement. Cell culturesAfter obtaining informed consent, human cord blood was taken from healthy donors and samples of blood were taken from patients with AML. This study was approved by the local ethical committees of the Italian National Institute of Health and the University of Tor Vergata.Cord blood CD34 + hematopoietic progenitor cell purification, unilineage monocytic differentiation and morphological analyses were performed as previously described. 39 Human primary AML-M5 blasts were maintained in culture in vitro in Iscove medium supplemented with 10% fetal calf serum, granulocyte-macrophage colony-stimulating factor (10 ng/mL), stem cell factor (50 ng/mL), and interleukin-3 (10 ng/mL) (PeproTech Inc. Rocky Hill, NJ, USA). RNA and protein samples were prepared as described elsewhere. 39 Leukemic cell lines, U937 and HL-60, were grown in RPMI medium supplemented with 10% fetal calf serum (Gibco, Carlsbad, CA, USA). HypoxiaTo provide a mild or more severe hypoxic environment, acute ...

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Macrophage development from HSCs requires PU.1-coordinated microRNA expression

Cited by 109 publications

References 54 publications

The microRNA-342-5p Fosters Inflammatory Macrophage Activation Through an Akt1- and microRNA-155 –Dependent Pathway During Atherosclerosis

The microRNA-342-5p Fosters Inflammatory Macrophage Activation Through an Akt1- and microRNA-155 –Dependent Pathway During Atherosclerosis

Architecture of a lymphomyeloid developmental switch controlled by PU.1, Notch and Gata3

Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells: impact on response to chemotherapy

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