End-stage differentiation of neutrophil granulocytes in vivo is accompanied by up-regulation of p27kip1 and down-regulation of CDK2, CDK4, and CDK6

Klausen, Pia; Bjerregaard, Malene Digmann; Borregaard, Niels; Cowland, Jack B.

doi:10.1189/jlb.1003474

Cited by 57 publications

(70 citation statements)

References 64 publications

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“…The proliferation ceases as these cells mature into metamyelocytes, band cells, and segmented neutrophils. 21,22 The mitotic pool of immature neutrophil precursors in the bone marrow of Atg5 NΔ mice exhibited a significantly higher proliferation rate when compared with WT mice, whereas the proliferation rate of mature neutrophils was, as expected, comparably low in all genotypes (Figure 2b). Atg5 mRNA expression in these immature neutrophil populations was reduced by 75.3 ± 18.9% compared with WT mice (Figure 1a).…”

Section: Lyz2mentioning

confidence: 82%

The generation of neutrophils in the bone marrow is controlled by autophagy

et al. 2014

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Autophagy has been demonstrated to have an essential function in several cellular hematopoietic differentiation processes, for example, the differentiation of reticulocytes. To investigate the role of autophagy in neutrophil granulopoiesis, we studied neutrophils lacking autophagy-related (Atg) 5, a gene encoding a protein essential for autophagosome formation. Using Cre-recombinase mediated gene deletion, Atg5-deficient neutrophils showed no evidence of abnormalities in morphology, granule protein content, apoptosis regulation, migration, or effector functions. In such mice, however, we observed an increased proliferation rate in the neutrophil precursor cells of the bone marrow as well as an accelerated process of neutrophil differentiation, resulting in an accumulation of mature neutrophils in the bone marrow, blood, spleen, and lymph nodes. To directly study the role of autophagy in neutrophils, we employed an in vitro model of differentiating neutrophils that allowed modulating the levels of ATG5 expression, or, alternatively, intervening pharmacologically with autophagy-regulating drugs. We could show that autophagic activity correlated inversely with the rate of neutrophil differentiation. Moreover, pharmacological inhibition of p38 MAPK or mTORC1 induced autophagy in neutrophilic precursor cells and blocked their differentiation, suggesting that autophagy is negatively controlled by the p38 MAPK-mTORC1 signaling pathway. On the other hand, we obtained no evidence for an involvement of the PI3K-AKT or ERK1/2 signaling pathways in the regulation of neutrophil differentiation. Taken together, these findings show that, in contrast to erythropoiesis, autophagy is not essential for neutrophil granulopoiesis, having instead a negative impact on the generation of neutrophils. Thus, autophagy and differentiation exhibit a reciprocal regulation by the p38-mTORC1 axis. Autophagy is an evolutionarily conserved mechanism, by which portions of cytoplasm are engulfed in a doublemembrane structure, known as the autophagosome, and delivered to lysosomes for subsequent degradation. Autophagy is dependent on autophagy-related (ATG) proteins. 1Autophagosome formation, elongation, and completion of enclosure require two ubiquitin-like conjugation systems: the first one generates the ATG5-ATG12 conjugate, which functions as a complex together with ATG16, and binds to the sequestering (pre-autophagosomal) phagophore. The second system conjugates an ATG8 homolog, LC3-I, with phosphatidylethanolamine to generate the lipidated LC3-II that associates with autophagosomes.2-4 The conversion of LC3-I into LC3-II represents a hallmark of autophagic activity and is widely used for the detection of autophagosome formation. Another frequently used marker for monitoring autophagic activity is p62, a protein, which is specifically degraded through autophagy. 5The vital role of autophagy in cell growth, development, and homeostasis has long been appreciated. Recent data also indicate its involvement in the differentiation of hematopoietic c...

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Section: Lyz2mentioning

confidence: 82%

The generation of neutrophils in the bone marrow is controlled by autophagy

et al. 2014

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“…19,30 Rapid down-regulation of p27 Kip1 is observed after stimulation with growth factors, when cells re-enter the cell cycle. 31 This suggests that IL-15MF and IL-15 tg MF are highly proliferating cells, which in addition are protected from apoptosis by IL-15.…”

Section: Il-15 Overexpression In Vivo Results In Highly Activated Mf mentioning

confidence: 99%

“…Reasoning that the enhanced MF activity leading to improved CD4 + T-cell stimulation could be the result of an altered expression of cell-cycle regulators, we next analysed the message expression (which correlates with the protein expression 19 ) of two critical cyclin-dependent kinase inhibitors. This revealed that p21 Waf1 , which protects MF from apop-tosis, 20 is expressed in MF and IL-15MF at comparable levels (Fig.…”

Section: Il-15 Regulates Expression Of the Cell-cycle Regulators P21 mentioning

confidence: 99%

Interleukin‐15 stimulates macrophages to activate CD4⁺ T cells: a role in the pathogenesis of rheumatoid arthritis?

et al. 2008

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Interleukin-15 stimulates macrophages to activate CD4 + T cells: a role in the pathogenesis of rheumatoid arthritis?Introduction ) is expressed in a wide variety of cell types, including fibroblasts, keratinocytes, epithelial cells, osteoclasts and activated monocytes. It is also produced by haematopoietic progenitors and bone marrow stromal cells 1 and by differentiated antigen-presenting cells and phagocytes, such as dendritic cells (DCs) and macrophages (MF). 2 We have reported that interaction between IL-15 and the IL-15 receptor a (IL-15Ra) in DCs is critical for maturation and antigen presentation to T cells. 3,4 Studies with IL-15Ra )/) and IL-15 )/) mice show that IL-15 is an essential cytokine for the development and survival of natural killer (NK) cells, NK T cells, and memory and activated CD8 + T cells. Interleukin-15 is a potent proinflammatory cytokine that induces, for example, tumour necrosis factor-a (TNF-a), IL-1b and inflammatory chemokines. It inhibits self-tolerance and facilitates the maintenance of memory T-cell survival, including that of self-directed cells. Deregulated IL-15 expression has been reported in patients with an array of inflammatory autoimmune diseases. SummaryInterleukin-15 (IL-15) is a proinflammatory cytokine that is overexpressed in rheumatoid arthritis (RA), a disease characterized by activation of monocytes/macrophages (MF), and by expansion of autoreactive CD4 + T cells. We hypothesized that IL-15 plays a major role for this expansion of CD4 + T cells and modulates the phenotype of monocytes/MF and their interaction with CD4 + T cells. Here, we show that IL-15 enhances the proliferation of CD4 + T cells from patients with RA in peripheral blood mononuclear cell cocultures. To further dissect the underlying mechanisms, we employed MF from IL-15 )/) or IL-15 transgenic mice. These were induced to differentiate or were stimulated with IL-15. Here we show that addition of IL-15 during differentiation of MF (into 'IL-15MF') and overexpression of IL-15 by MF from IL-15 tg mice leads to increased levels of major histocompatibility complex class II expression. This resulted in enhanced stimulation of antigen-specific CD4 + T cells in vitro and was accompanied by reduced messenger RNA expression in MF for immunosuppressive SOCS3. The proliferation rates of IL-15MF and IL-15 tg MF were high, which was reflected by increased p27 Kip1 and reduced p21 Waf1 levels. In view of high serum and synovial levels of IL-15 in patients with RA, our data suggest the possibility that this excess IL-15 in RA may stimulate monocytes/MF to activate the characteristic autoreactive CD4 + T cells in RA.

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“…44 Expression of these molecules in mature neutrophils is likely at a much lower level than in precursor cells, as CDK2, CDK4 and CDK6 protein expression is largely diminished in mature neutrophils as compared with promyelocytes. 47 Nevertheless, treatment of neutrophils with R-roscovitine, an inhibitor of CDK2, CDK7 and CDK9, results in neutrophil apoptosis ex vivo and in the resolution of inflammation in established animal models. 44 As R-roscovitine was subsequently shown to downregulate protein expression of Mcl-1, 45 this drug likely modulates neutrophil lifespan by controlling the expression of Bcl-2 family members.…”

Section: Reactive Oxygen Species (Ros)mentioning

confidence: 99%

“…44 This finding was surprising, as neutrophils were previously shown to downregulate Cdks during differentiation to mature cells. 47 A peptide of the Cdk inhibitor p21 was furthermore shown to interfere with binding of PCNA to pro-caspases and to induce neutrophil apoptosis in vitro. 46 Thus, this p21 peptide might be a potent inducer of neutrophil apoptosis through interaction with PCNA, but also Cdks.…”

Section: Bv6mentioning

confidence: 99%

Peculiarities of cell death mechanisms in neutrophils

2011

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Analyses of neutrophil death mechanisms have revealed many similarities with other cell types; however, a few important molecular features make these cells unique executors of cell death mechanisms. For instance, in order to fight invading pathogens, neutrophils possess a potent machinery to produce reactive oxygen species (ROS), the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Evidence is emerging that these ROS are crucial in the execution of most neutrophil cell death mechanisms. Likewise, neutrophils exhibit many diverse granules that are packed with cytotoxic mediators. Of those, cathepsins were recently shown to activate pro-apoptotic B-cell lymphoma-2 (Bcl-2) family members and caspases, thus acting on apoptosis regulators. Moreover, neutrophils have few mitochondria, which hardly participate in ATP synthesis, as neutrophils gain energy from glycolysis. In spite of relatively low levels of cytochrome c in these cells, the mitochondrial death pathway is functional. In addition to these pecularities defining neutrophil death pathways, neutrophils are terminally differentiated cells, hence they do not divide but undergo apoptosis shortly after maturation. The initial trigger of this spontaneous apoptosis remains to be determined, but may result from low transcription and translation activities in mature neutrophils. Due to the unique biological characteristics of neutrophils, pharmacological intervention of inflammation has revealed unexpected and sometimes disappointing results when neutrophils were among the prime target cells during therapy. In this study, we review the current and emerging models of neutrophil cell death mechanisms with a focus on neutrophil peculiarities.

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End-stage differentiation of neutrophil granulocytes in vivo is accompanied by up-regulation of p27kip1 and down-regulation of CDK2, CDK4, and CDK6

Cited by 57 publications

References 64 publications

The generation of neutrophils in the bone marrow is controlled by autophagy

The generation of neutrophils in the bone marrow is controlled by autophagy

Interleukin‐15 stimulates macrophages to activate CD4⁺ T cells: a role in the pathogenesis of rheumatoid arthritis?

Peculiarities of cell death mechanisms in neutrophils

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End-stage differentiation of neutrophil granulocytes in vivo is accompanied by up-regulation of p27kip1 and down-regulation of CDK2, CDK4, and CDK6

Cited by 57 publications

References 64 publications

The generation of neutrophils in the bone marrow is controlled by autophagy

The generation of neutrophils in the bone marrow is controlled by autophagy

Interleukin‐15 stimulates macrophages to activate CD4+ T cells: a role in the pathogenesis of rheumatoid arthritis?

Peculiarities of cell death mechanisms in neutrophils

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Interleukin‐15 stimulates macrophages to activate CD4⁺ T cells: a role in the pathogenesis of rheumatoid arthritis?