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Frontiers in Immunology 2019Neutrophils are implicated in almost every stage of oncogenesis and paradoxically display anti- and pro-tumor properties. Accumulating evidence indicates that... (Review)
Review
Neutrophils are implicated in almost every stage of oncogenesis and paradoxically display anti- and pro-tumor properties. Accumulating evidence indicates that neutrophils display diversity in their phenotype resulting from functional plasticity and/or changes to granulopoiesis. In cancer, neutrophils at a range of maturation stages can be identified in the blood and tissues (i.e., outside of their developmental niche). The functional capacity of neutrophils at different states of maturation is poorly understood resulting from challenges in their isolation, identification, and investigation. Thus, the impact of neutrophil maturity on cancer progression and therapy remains enigmatic. In this review, we discuss the identification, prevalence, and function of immature and mature neutrophils in cancer and the potential impact of this on tumor progression and cancer therapy.
Topics: CCAAT-Binding Factor; Cell Differentiation; Disease Progression; Gene Expression Regulation, Neoplastic; Hematopoietic Stem Cells; Humans; Leukopoiesis; Neoplasms; Neutrophils; Proto-Oncogene Proteins; Trans-Activators
PubMed: 31474989
DOI: 10.3389/fimmu.2019.01912 -
Immunity Nov 2019Generation of the first T lymphocytes in the human embryo involves the emergence, migration, and thymus seeding of lymphoid progenitors together with concomitant thymus...
Generation of the first T lymphocytes in the human embryo involves the emergence, migration, and thymus seeding of lymphoid progenitors together with concomitant thymus organogenesis, which is the initial step to establish the entire adaptive immune system. However, the cellular and molecular programs regulating this process remain unclear. We constructed a single-cell transcriptional landscape of human early T lymphopoiesis by using cells from multiple hemogenic and hematopoietic sites spanning embryonic and fetal stages. Among heterogenous early thymic progenitors, one subtype shared common features with a subset of lymphoid progenitors in fetal liver that are known as thymus-seeding progenitors. Unbiased bioinformatics analysis identified a distinct type of pre-thymic lymphoid progenitors in the aorta-gonad-mesonephros (AGM) region. In parallel, we investigated thymic epithelial cell development and potential cell-cell interactions during thymus organogenesis. Together, our data provide insights into human early T lymphopoiesis that prospectively direct T lymphocyte regeneration, which might lead to development of clinical applications.
Topics: Biomarkers; Cell Differentiation; Embryo, Mammalian; Embryonic Development; Gene Expression Profiling; Hematopoietic Stem Cells; Humans; Immunophenotyping; Lymphopoiesis; Organogenesis; Precursor Cells, T-Lymphoid; Signal Detection, Psychological; T-Lymphocytes; Thymus Gland; Transcriptome
PubMed: 31604687
DOI: 10.1016/j.immuni.2019.09.008 -
Cell Oct 2020A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic...
A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis (Mtb). We have shown that systemic administration of Bacille Calmette-Guérin (BCG) or β-glucan reprograms HSCs in the bone marrow (BM) via a type II interferon (IFN-II) or interleukin-1 (IL1) response, respectively, which confers protective trained immunity against Mtb. Here, we demonstrate that, unlike BCG or β-glucan, Mtb reprograms HSCs via an IFN-I response that suppresses myelopoiesis and impairs development of protective trained immunity to Mtb. Mechanistically, IFN-I signaling dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death specifically in myeloid progenitors. Additionally, activation of the IFN-I/iron axis in HSCs impairs trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the BM that controls the magnitude and intrinsic anti-microbial capacity of innate immunity to infection.
Topics: Animals; Bone Marrow Cells; Cell Proliferation; Disease Susceptibility; Hematopoietic Stem Cells; Homeostasis; Immunity; Interferon Type I; Iron; Kinetics; Lung; Macrophages; Mice, Inbred C57BL; Mycobacterium tuberculosis; Myeloid Cells; Myelopoiesis; Necrosis; Signal Transduction; Transcription, Genetic; Tuberculosis
PubMed: 33125891
DOI: 10.1016/j.cell.2020.09.062 -
Cell Reports Mar 2023Inflammatory stimuli cause a state of emergency myelopoiesis leading to neutrophil-like monocyte expansion. However, their function, the committed precursors, or growth...
Inflammatory stimuli cause a state of emergency myelopoiesis leading to neutrophil-like monocyte expansion. However, their function, the committed precursors, or growth factors remain elusive. In this study we find that Ym1Ly6C monocytes, an immunoregulatory entity of neutrophil-like monocytes, arise from progenitors of neutrophil 1 (proNeu1). Granulocyte-colony stimulating factor (G-CSF) favors the production of neutrophil-like monocytes through previously unknown CD81CX3CR1 monocyte precursors. GFI1 promotes the differentiation of proNeu2 from proNeu1 at the cost of producing neutrophil-like monocytes. The human counterpart of neutrophil-like monocytes that also expands in response to G-CSF is found in CD14CD16 monocyte fraction. The human neutrophil-like monocytes are discriminated from CD14CD16 classical monocytes by CXCR1 expression and the capacity to suppress T cell proliferation. Collectively, our findings suggest that the aberrant expansion of neutrophil-like monocytes under inflammatory conditions is a process conserved between mouse and human, which may be beneficial for the resolution of inflammation.
Topics: Mice; Animals; Humans; Monocytes; Neutrophils; Myelopoiesis; Cell Differentiation; Granulocyte Colony-Stimulating Factor
PubMed: 36862552
DOI: 10.1016/j.celrep.2023.112165 -
Current Opinion in Lipidology Oct 2019Monocytes and macrophages are key players in the pathogenesis of atherosclerosis and dictate atherogenesis growth and stability. The heterogeneous nature of myeloid... (Review)
Review
PURPOSE OF REVIEW
Monocytes and macrophages are key players in the pathogenesis of atherosclerosis and dictate atherogenesis growth and stability. The heterogeneous nature of myeloid cells concerning their metabolic and phenotypic function is increasingly appreciated. This review summarizes the recent monocyte and macrophage literature and highlights how differing subsets contribute to atherogenesis.
RECENT FINDINGS
Monocytes are short-lived cells generated in the bone marrow and released to circulation where they can produce inflammatory cytokines and, importantly, differentiate into long-lived macrophages. In the context of cardiovascular disease, a myriad of subtypes, exist with each differentially contributing to plaque development. Herein we describe recent novel characterizations of monocyte and macrophage subtypes and summarize the recent literature on mediators of myelopoiesis.
SUMMARY
An increased understanding of monocyte and macrophage phenotype and their molecular regulators is likely to translate to the development of new therapeutic targets to either stem the growth of existing plaques or promote plaque stabilization.
Topics: Atherosclerosis; Bone Marrow Cells; Cell Differentiation; Cytokines; Humans; Macrophages; Monocytes; Myelopoiesis; Plaque, Atherosclerotic
PubMed: 31361625
DOI: 10.1097/MOL.0000000000000634 -
Frontiers in Immunology 2021Germinal Centres (GCs) are transient structures in secondary lymphoid organs, where affinity maturation of B cells takes place following an infection. While GCs are... (Review)
Review
Germinal Centres (GCs) are transient structures in secondary lymphoid organs, where affinity maturation of B cells takes place following an infection. While GCs are responsible for protective antibody responses, dysregulated GC reactions are associated with autoimmune disease and B cell lymphoma. Typically, 'normal' GCs persist for a limited period of time and eventually undergo shutdown. In this review, we focus on an important but unanswered question - what causes the natural termination of the GC reaction? In murine experiments, lack of antigen, absence or constitutive T cell help leads to premature termination of the GC reaction. Consequently, our present understanding is limited to the idea that GCs are terminated due to a decrease in antigen access or changes in the nature of T cell help. However, there is no direct evidence on which biological signals are primarily responsible for natural termination of GCs and a mechanistic understanding is clearly lacking. We discuss the present understanding of the GC shutdown, from factors impacting GC dynamics to changes in cellular interactions/dynamics during the GC lifetime. We also address potential missing links and remaining questions in GC biology, to facilitate further studies to promote a better understanding of GC shutdown in infection and immune dysregulation.
Topics: Animals; Antibodies; Antigen Presentation; Apoptosis; B-Lymphocyte Subsets; Cell Division; Cell Lineage; Cytokines; Dendritic Cells, Follicular; Feedback, Physiological; Gene Rearrangement, B-Lymphocyte; Germinal Center; Humans; Infections; Lymphoma, B-Cell; Lymphopoiesis; Macrophages; Memory B Cells; Mice; Models, Immunological; Plasma Cells; Vaccines
PubMed: 34305944
DOI: 10.3389/fimmu.2021.705240 -
FASEB Journal : Official Publication of... Jun 2020The medical, public health, and scientific communities are grappling with monumental imperatives to contain COVID-19, develop effective vaccines, identify efficacious...
The medical, public health, and scientific communities are grappling with monumental imperatives to contain COVID-19, develop effective vaccines, identify efficacious treatments for the infection and its complications, and find biomarkers that detect patients at risk of severe disease. The focus of this communication is on a potential biomarker, short telomere length (TL), that might serve to identify patients more likely to die from the SARS-CoV-2 infection, regardless of age. The common thread linking these patients is lymphopenia, which largely reflects a decline in the numbers of CD4/CD8 T cells but not B cells. These findings are consistent with data that lymphocyte TL dynamics impose a limit on T-cell proliferation. They suggest that T-cell lymphopoiesis might stall in individuals with short TL who are infected with SARS-CoV-2.
Topics: Betacoronavirus; Biomarkers; Bone Marrow; COVID-19; Cell Division; Coronavirus Infections; Disease Progression; Hematopoietic Stem Cells; Humans; Lymphocyte Activation; Lymphocyte Count; Lymphopenia; Lymphopoiesis; Models, Biological; Pandemics; Pneumonia, Viral; Prognosis; Risk; SARS-CoV-2; T-Lymphocyte Subsets; Telomere; Telomere Shortening
PubMed: 32427393
DOI: 10.1096/fj.202001025 -
Cells Dec 2020Fibronectin is a ubiquitous extracellular matrix protein that is produced by many cell types in the bone marrow and distributed throughout it. Cells of the stem cell... (Review)
Review
Fibronectin is a ubiquitous extracellular matrix protein that is produced by many cell types in the bone marrow and distributed throughout it. Cells of the stem cell niche produce the various isoforms of this protein. Fibronectin not only provides the cells a scaffold to bind to, but it also modulates their behavior by binding to receptors on the adjacent hematopoietic stem cells and stromal cells. These receptors, which include integrins such as α4β1, α9β1, α4β7, α5β1, αvβ3, Toll-like receptor-4 (TLR-4), and CD44, are found on the hematopoietic stem cell. Because the knockout of fibronectin is lethal during embryonal development and because fibronectin is produced by almost all cell types in mammals, the study of its role in hematopoiesis is difficult. Nevertheless, strong and direct evidence exists for its stimulation of myelopoiesis and thrombopoiesis using in vivo models. Other reviewed effects can be deduced from the study of fibronectin receptors, which showed their activation modifies the behavior of hematopoietic stem cells. Erythropoiesis was only stimulated under hemolytic stress, and mostly late stages of lymphocytic differentiation were modulated. Because fibronectin is ubiquitously expressed, these interactions in health and disease need to be taken into account whenever any molecule is evaluated in hematopoiesis.
Topics: Animals; Cell Differentiation; Cell Movement; Cell Proliferation; Erythropoiesis; Fibronectins; Hematopoiesis; Hematopoietic Stem Cells; Hemolysis; Humans; Hyaluronan Receptors; Integrins; Mice; Myelopoiesis; Receptors, Fibronectin; Stem Cell Niche; Stem Cells; Thrombopoiesis; Toll-Like Receptor 4
PubMed: 33353083
DOI: 10.3390/cells9122717 -
Frontiers in Immunology 2022During acute infectious and inflammatory conditions, a large number of neutrophils are in high demand as they are consumed in peripheral organs. The hematopoietic system... (Review)
Review
During acute infectious and inflammatory conditions, a large number of neutrophils are in high demand as they are consumed in peripheral organs. The hematopoietic system rapidly responds to the demand by turning from steady state to emergency granulopoiesis to expedite neutrophil generation in the bone marrow (BM). How the hematopoietic system integrates pathogenic and inflammatory stress signals into the molecular cues of emergency granulopoiesis has been the subject of investigations. Recent studies in the field have highlighted emerging concepts, including the direct sensing of pathogens by BM resident or sentinel hematopoietic stem and progenitor cells (HSPCs), the crosstalk of HSPCs, endothelial cells, and stromal cells to convert signals to granulopoiesis, and the identification of novel inflammatory molecules, such as C/EBP-β, ROS, IL-27, IFN-γ, CXCL1 with direct effects on HSPCs. In this review, we will provide a detailed account of emerging concepts while reassessing well-established cellular and molecular players of emergency granulopoiesis. While providing our views on the discrepant results and theories, we will postulate an updated model of granulopoiesis in the context of health and disease.
Topics: Endothelial Cells; Hematopoiesis; Interleukin-27; Leukopoiesis; Reactive Oxygen Species
PubMed: 36148240
DOI: 10.3389/fimmu.2022.961601 -
International Journal of Hematology May 2020It has been over 35 years since the discovery of a special subtype of B cells in mice. These IgM B cells are named B-1 cells, whereas conventional B cells are referred... (Review)
Review
It has been over 35 years since the discovery of a special subtype of B cells in mice. These IgM B cells are named B-1 cells, whereas conventional B cells are referred to as B-2 cells. B-1 cells express Ly-1 (CD5) and CD11b antigen, which are usually expressed in T cells and myeloid cells, respectively, reside mainly in the peritoneal and pleural cavities, and secrete natural IgM antibodies in a T cell-independent manner. B-1 cells are further categorized into CD5 B-1a cells and CD5 B-1b cells. B-1 cells may develop through positive selection and secrete natural antibodies, including low-affinity-binding autoantibodies. Transplantation assays have revealed that the fetal liver, not the bone marrow (BM), is a major site for the production of B-1a cells, leading to the concept of a fetal origin for B-1a cells. This review introduces how the origin of B-1a cells has been explored, and describes the current state of knowledge gained through various approaches.
Topics: Animals; B-Lymphocyte Subsets; Bone Marrow Cells; CD5 Antigens; Cell Transplantation; Hematopoiesis; Hematopoietic Stem Cells; Humans; Immunoglobulin M; Liver; Lymphopoiesis; Mice; Precursor Cells, B-Lymphoid; RNA-Binding Proteins
PubMed: 31802412
DOI: 10.1007/s12185-019-02787-8