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Leukemia & Lymphoma Jul 2003Neutrophils, monocytes and dendritic cells are effectors of innate immunity and essential coactivators in the acquired immune response. Understanding the biochemical... (Review)
Review
Estrogen-regulated conditional oncoproteins: tools to address open questions in normal myeloid cell function, normal myeloid differentiation, and the genetic basis of differentiation arrest in myeloid leukemia.
Neutrophils, monocytes and dendritic cells are effectors of innate immunity and essential coactivators in the acquired immune response. Understanding the biochemical basis of their mature cell functions, their differentiation from hematopoietic progenitors, and the mechanisms by which myeloid leukemia oncogenes block their differentiation programs, continue to be areas of active research. Four major problems limit progress in these fields. First, the biochemical analysis of mature cells is limited by the time and cost of purifying neutrophils, monocytes, or dendritic cells from wild-type and genetically modified mouse strains. Second, while immortal myeloid cell lines are used to understand the transcriptional basis of normal terminal differentiation following their treatment with differentiationpromoting agents (e.g. G-CSF, IL-6, RA, TPA), these cells contain stable defects responsible for their immortalization, and the degree to which they model normal differentiation is often incomplete. Third, these same inducible cell lines are used as model systems to determine how myeloid oncoproteins prevent differentiation; however, oncoproteins that block differentiation of marrow progenitors cultured in GM-CSF or IL-3 but permit their differentiation in response to G-CSF or RA, do not score effectively in these assays (e.g. Hoxa9, Mll-Enl). Fourth, there is no reproducible method to derive myeloid progenitor lines that execute predictable terminal differentiation to neutrophils, monocytes, or dendritic cells. Developing this type of system is needed to evaluate how myeloid gene inactivation by knockout technologies alters lineage-specific differentiation and mature cell function. Conditional myeloid oncoproteins provide a tool to solve these research problems by providing a predictable and inexpensive means of expanding, in culture, GM-CSF- or IL-3-dependent myeloid progenitors from any genotype, and by permitting their synchronous differentiation to neutrophils, monocytes, or dendritic cells under defined culture conditions following inactivation of the conditional oncoprotein. This system of conditionally immortalizing normal bone marrow precursors provides the large numbers of normal cells required for analysis of cell biology and protein biochemistry, and further provides a model system in which to study the genetic mechanisms controlling terminal differentiation and how specific oncoproteins expressed in the cell lines prevent this differentiation program. The ability to derive conditionally-immortalized progenitor lines from knock-out mice provides cell lines for the reconstitution of knockout gene function and subsequent dissection of knockout protein function by mutational analysis. Finally, conditional myeloid cell lines can be established from both ES cells and from d10 fetal liver cells, allowing for the analysis of embryonic lethal mutants on both the maturation and terminal differentiation of mature myeloid cells. In this review,we summarize the importance and limitations of current approaches in myeloid cell research, and how estrogen-regulated conditional oncoproteins help to solve these problems.
Topics: Animals; Cell Differentiation; Cell Division; Cytokines; Estrogens; Gene Expression Regulation, Leukemic; Humans; Leukemia, Myeloid; Myeloid Cells; Oncogene Proteins; Receptors, Estrogen
PubMed: 12916864
DOI: 10.1080/1042819031000063444 -
International Immunopharmacology Jul 2011Tumor growth is often associated with the aberrant systemic accumulation of myeloid-derived suppressor cells (MDSCs), which are a heterogenous population of cells... (Review)
Review
Tumor growth is often associated with the aberrant systemic accumulation of myeloid-derived suppressor cells (MDSCs), which are a heterogenous population of cells composed of polymorphonuclear neutrophils, monocytes, macrophages, dendritic cells and early myeloid precursors. These MDSCs are thought to suppress anti-tumor T cell responses in both tumor tissues and secondary lymphoid tissues. Accumulation of MDSCs in these target tissues is a dynamic process associated with medullary and extramedullary myelopoiesis and subsequent cellular migration. Here, we review the current understanding of the cellular, molecular, hematological and anatomical principles of MDSC development and migration in tumor-bearing mice. We also discuss the therapeutic potential of chemokines that influence the balance between MDSC subpopulations.
Topics: Animals; Cell Communication; Cell Lineage; Cell Movement; Chemokines; Humans; Immunosuppression Therapy; Mice; Myeloid Cells; Myelopoiesis; Neoplasms, Experimental; T-Lymphocytes
PubMed: 21406269
DOI: 10.1016/j.intimp.2011.03.003 -
Journal of Internal Medicine May 2019Myeloid cells assume a wide range of phenotypes, some of which are protective against injury and infection whilst others promote cardiovascular disease. This... (Review)
Review
Myeloid cells assume a wide range of phenotypes, some of which are protective against injury and infection whilst others promote cardiovascular disease. This heterogeneity is partially caused by switching of cell sources from local tissue-resident macrophage proliferation to recruitment of circulating cells, and partially due to macrophages' phenotypic plasticity. While long-lived tissue-resident macrophages support development, tissue homoeostasis and cardiac conduction, monocyte-derived cells may promote destruction of the arterial wall and the myocardium, leading to organ ischaemia and heart failure. Influencing myeloid cell flux and phenotype shifts emerges as a therapeutic opportunity in many disease areas, including atherosclerosis, acute myocardial infarction, heart failure and stroke. However, it is currently unclear which cell subsets and drug targets are the most efficient and safest options. Here I review the neutrophil and macrophage supply chain and the cells' emerging heterogeneity in the setting of atherosclerosis and ischaemic heart disease.
Topics: Atherosclerosis; Cardiovascular Diseases; Humans; Myeloid Cells; Myocardial Ischemia
PubMed: 30585362
DOI: 10.1111/joim.12844 -
Microbiology Spectrum Jan 2017Asthma is a heterogeneous chronic inflammatory disorder of the airways, and not surprisingly, many myeloid cells play a crucial role in pathogenesis. Antigen-presenting... (Review)
Review
Asthma is a heterogeneous chronic inflammatory disorder of the airways, and not surprisingly, many myeloid cells play a crucial role in pathogenesis. Antigen-presenting dendritic cells are the first to recognize the allergens, pollutants, and viruses that are implicated in asthma pathogenesis, and subsequently initiate the adaptive immune response by migrating to lymph nodes. Eosinophils are the hallmark of type 2 inflammation, releasing toxic compounds in the airways and contributing to airway remodeling. Mast cells and basophils control both the early- and late-phase allergic response and contribute to alterations in smooth muscle reactivity. Finally, relatively little is known about neutrophils and macrophages in this disease. Although many of these myeloid cells respond well to treatment with inhaled steroids, there is now an increasing armamentarium of targeted biologicals that can specifically eliminate only one myeloid cell population, like eosinophils. It is only with those new tools that we will be able to fully understand the role of myeloid cells in chronic asthma in humans.
Topics: Animals; Asthma; Chronic Disease; Humans; Myeloid Cells
PubMed: 28102118
DOI: 10.1128/microbiolspec.MCHD-0053-2016 -
Blood Nov 2021Histone H3 lysine 4 methylation (H3K4Me) is most often associated with chromatin activation, and removing H3K4 methyl groups has been shown to be coincident with gene...
Histone H3 lysine 4 methylation (H3K4Me) is most often associated with chromatin activation, and removing H3K4 methyl groups has been shown to be coincident with gene repression. H3K4Me demethylase KDM1a/LSD1 is a therapeutic target for multiple diseases, including for the potential treatment of β-globinopathies (sickle cell disease and β-thalassemia), because it is a component of γ-globin repressor complexes, and LSD1 inactivation leads to robust induction of the fetal globin genes. The effects of LSD1 inhibition in definitive erythropoiesis are not well characterized, so we examined the consequences of conditional inactivation of Lsd1 in adult red blood cells using a new Gata1creERT2 bacterial artificial chromosome transgene. Erythroid-specific loss of Lsd1 activity in mice led to a block in erythroid progenitor differentiation and to the expansion of granulocyte-monocyte progenitor-like cells, converting hematopoietic differentiation potential from an erythroid fate to a myeloid fate. The analogous phenotype was also observed in human hematopoietic stem and progenitor cells, coincident with the induction of myeloid transcription factors (eg, PU.1 and CEBPα). Finally, blocking the activity of the transcription factor PU.1 or RUNX1 at the same time as LSD1 inhibition rescued myeloid lineage conversion to an erythroid phenotype. These data show that LSD1 promotes erythropoiesis by repressing myeloid cell fate in adult erythroid progenitors and that inhibition of the myeloid-differentiation pathway reverses the lineage switch induced by LSD1 inactivation.
Topics: Animals; Cell Line; Cells, Cultured; Erythroid Cells; Erythropoiesis; Gene Deletion; Histone Demethylases; Humans; Mice; Myeloid Cells
PubMed: 34324630
DOI: 10.1182/blood.2021011682 -
Journal of Cellular and Molecular... Aug 2019A novel myeloid antigen presenting cell can be generated through in vitro haematopoiesis in long-term splenic stromal cocultures. The in vivo equivalent subset was...
A novel myeloid antigen presenting cell can be generated through in vitro haematopoiesis in long-term splenic stromal cocultures. The in vivo equivalent subset was recently identified as phenotypically and functionally distinct from the spleen subsets of macrophages, conventional (c) dendritic cells (DC), resident monocytes, inflammatory monocytes and eosinophils. This novel subset which is myeloid on the basis of cell surface phenotype, but dendritic-like on the basis of cell surface marker expression and antigen presenting function, has been tentatively labelled "L-DC." Transcriptome analysis has now been employed to determine the lineage relationship of this cell type with known splenic cDC and monocyte subsets. Principal components analysis showed separation of "L-DC" and monocytes from cDC subsets in the second principal component. Hierarchical clustering then indicated a close lineage relationship between this novel subset, resident monocytes and inflammatory monocytes. Resident monocytes were the most closely aligned, with no genes specifically expressed by the novel subset. This subset, however, showed upregulation of genes reflecting both dendritic and myeloid lineages, with strong upregulation of several genes, particularly CD300e. While resident monocytes were found to be dependent on Toll-like receptor signalling for development and were reduced in number in Myd88-/- and Trif-/- mutant mice, both the novel subset and inflammatory monocytes were unaffected. Here, we describe a novel myeloid cell type closely aligned with resident monocytes in terms of lineage but distinct in terms of development and functional capacity.
Topics: Animals; Antigen Presentation; Antigen-Presenting Cells; Cell Differentiation; Cell Lineage; Coculture Techniques; Dendritic Cells; Eosinophils; Gene Expression Profiling; Hematopoiesis; Lymphocyte Activation; Mice; Monocytes; Myeloid Cells; Myeloid Progenitor Cells; Spleen
PubMed: 31210415
DOI: 10.1111/jcmm.14382 -
Cancer Cell Dec 2017Increased oxidative stress has been suggested to initiate and promote tumorigenesis by inducing DNA damage and to suppress tumor development by triggering apoptosis and...
Increased oxidative stress has been suggested to initiate and promote tumorigenesis by inducing DNA damage and to suppress tumor development by triggering apoptosis and senescence. The contribution of individual cell types in the tumor microenvironment to these contrasting effects remains poorly understood. We provide evidence that during intestinal tumorigenesis, myeloid cell-derived HO triggers genome-wide DNA mutations in intestinal epithelial cells to stimulate invasive growth. Moreover, increased reactive oxygen species (ROS) production in myeloid cells initiates tumor growth in various organs also in the absence of a carcinogen challenge in a paracrine manner. Our data identify an intricate crosstalk between myeloid cell-derived ROS molecules, oxidative DNA damage, and tumor necrosis factor α-mediated signaling to orchestrate a tumor-promoting microenvironment causing invasive cancer.
Topics: Animals; Apoptosis; DNA Damage; Epithelial Cells; Hydrogen Peroxide; Mice; Mice, Mutant Strains; Mutagenesis; Mutation; Myeloid Cells; Oxidative Stress; Reactive Oxygen Species; Signal Transduction
PubMed: 29232557
DOI: 10.1016/j.ccell.2017.11.004 -
Frontiers in Immunology 2019Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) is a myelopoietic growth factor that has pleiotropic effects not only in promoting the differentiation of... (Review)
Review
Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) is a myelopoietic growth factor that has pleiotropic effects not only in promoting the differentiation of immature precursors into polymorphonuclear neutrophils (PMNs), monocytes/macrophages (MØs) and dendritic cells (DCs), but also in controlling the function of fully mature myeloid cells. This broad spectrum of GM-CSF action may elicit paradoxical outcomes-both immunostimulation and immunosuppression-in infection, inflammation, and cancer. The complexity of GM-CSF action remains to be fully unraveled. Several aspects of GM-CSF action could contribute to its diverse biological consequences. Firstly, GM-CSF as a single cytokine affects development of most myeloid cells from progenitors to mature immune cells. Secondly, GM-CSF activates JAK2/STAT5 and also activate multiple signaling modules and transcriptional factors that direct different biological processes. Thirdly, GM-CSF can be produced by different cell types including tumor cells in response to different environmental cues; thus, GM-CSF quantity can vary greatly under different pathophysiological settings. Finally, GM-CSF signaling is also fine-tuned by other less defined feedback mechanisms. In this review, we will discuss the role of GM-CSF in orchestrating the differentiation, survival, and proliferation during the generation of multiple lineages of myeloid cells (PMNs, MØs, and DCs). We will also discuss the role of GM-CSF in regulating the function of DCs and the functional polarization of MØs. We highlight how the dose of GM-CSF and corresponding signal strength acts as a rheostat to fine-tune cell fate, and thus the way GM-CSF may best be targeted for immuno-intervention in infection, inflammation and cancer.
Topics: Animals; Cell Differentiation; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Myeloid Cells
PubMed: 31803190
DOI: 10.3389/fimmu.2019.02679 -
Immunological Reviews Mar 2009Lyn is an Src family kinase present in B lymphocytes and myeloid cells. In these cell types, Lyn establishes signaling thresholds by acting as both a positive and a... (Review)
Review
Lyn is an Src family kinase present in B lymphocytes and myeloid cells. In these cell types, Lyn establishes signaling thresholds by acting as both a positive and a negative modulator of a variety of signaling responses and effector functions. Lyn deficiency in mice results in the development of myeloproliferation and autoimmunity. The latter has been attributed to the hyper-reactivity of Lyn-deficient B cells due to the unique role of Lyn in downmodulating B-cell receptor activation, mainly through phosphorylation of inhibitory molecules and receptors. Myeloproliferation results, on the other hand, from the enhanced sensitivity of Lyn-deficient progenitors to a number of colony-stimulating factors (CSFs). The hyper-sensitivity to myeloid growth factors may also be secondary to poor inhibitory receptor phosphorylation, leading to impaired recruitment/activation of tyrosine phosphatases and reduced downmodulation of CSF signaling responses. Despite these observations, the overall role of Lyn in the modulation of myeloid cell effector functions is much less well understood, as often both positive and negative roles of this kinase have been reported. In this review, we discuss the current knowledge of the duplicitous nature of Lyn in the modulation of myeloid cell signaling and function.
Topics: Animals; Blood Cells; Humans; Immune System; Myeloid Cells; Signal Transduction; src-Family Kinases
PubMed: 19290919
DOI: 10.1111/j.1600-065X.2008.00758.x -
International Journal of Hematology Apr 2015
Topics: Gene Expression Regulation, Developmental; Hematopoiesis; Humans; Myeloid Cells; Transcriptional Activation
PubMed: 25753224
DOI: 10.1007/s12185-015-1770-8