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International Journal of Molecular... Jun 2022The Class III receptor tyrosine kinase Flt3 and its ligand, the Flt3-ligand (FL), play an integral role in regulating the proliferation, differentiation, and survival of... (Review)
Review
The Class III receptor tyrosine kinase Flt3 and its ligand, the Flt3-ligand (FL), play an integral role in regulating the proliferation, differentiation, and survival of multipotent hematopoietic and lymphoid progenitors from which B cell precursors derive in bone marrow (BM). More recently, essential roles for Flt3 signaling in the regulation of peripheral B cell development and affinity maturation have come to light. Experimental findings derived from a multitude of mouse models have reinforced the importance of molecular and cellular regulation of Flt3 and FL in lymphohematopoiesis and adaptive immunity. Here, we provide a comprehensive review of the current state of the knowledge regarding molecular and cellular regulation of Flt3/FL and the roles of Flt3 signaling in hematopoietic stem cell (HSC) activation, lymphoid development, BM B lymphopoiesis, and peripheral B cell development. Cumulatively, the literature has reinforced the importance of Flt3 signaling in B cell development and function. However, it has also identified gaps in the knowledge regarding Flt3-dependent developmental-stage specific gene regulatory circuits essential for steady-state B lymphopoiesis that will be the focus of future studies.
Topics: Animals; B-Lymphocytes; Cell Differentiation; Hematopoietic Stem Cells; Immunity, Humoral; Ligands; Lymphopoiesis; Mice; fms-Like Tyrosine Kinase 3
PubMed: 35806293
DOI: 10.3390/ijms23137289 -
Proceedings of the National Academy of... Oct 2021Trained immunity defines long-lasting adaptations of innate immunity based on transcriptional and epigenetic modifications of myeloid cells and their bone marrow...
Trained immunity defines long-lasting adaptations of innate immunity based on transcriptional and epigenetic modifications of myeloid cells and their bone marrow progenitors [M. Divangahi et al., 22, 2-6 (2021)]. Innate immune cells, however, do not exclusively differentiate between foreign and self but also react to host-derived molecules referred to as alarmins. Extracellular "labile" heme, released during infections, is a bona fide alarmin promoting myeloid cell activation [M. P. Soares, M. T. Bozza, 38, 94-100 (2016)]. Here, we report that labile heme is a previously unrecognized inducer of trained immunity that confers long-term regulation of lineage specification of hematopoietic stem cells and progenitor cells. In contrast to previous reports on trained immunity, essentially mediated by pathogen-associated molecular patterns, heme training depends on spleen tyrosine kinase signal transduction pathway acting upstream of c-Jun N-terminal kinases. Heme training promotes resistance to sepsis, is associated with the expansion of self-renewing hematopoetic stem cells primed toward myelopoiesis and to the occurrence of a specific myeloid cell population. This is potentially evoked by sustained activity of Nfix, Runx1, and Nfe2l2 and dissociation of the transcriptional repressor Bach2. Previously reported trained immunity inducers are, however, infrequently present in the host, whereas heme abundantly occurs during noninfectious and infectious disease. This difference might explain the vanishing protection exerted by heme training in sepsis over time with sustained long-term myeloid adaptations. Hence, we propose that trained immunity is an integral component of innate immunity with distinct functional differences on infectious disease outcome depending on its induction by pathogenic or endogenous molecules.
Topics: Animals; Epigenesis, Genetic; Heme; Humans; Immunity, Innate; Mice; Myelopoiesis
PubMed: 34663697
DOI: 10.1073/pnas.2102698118 -
Genes May 2021The mechanistic target of rapamycin (mTOR) controls cell fate and responses via its functions in regulating metabolism. Its role in controlling immunity was unraveled by... (Review)
Review
The mechanistic target of rapamycin (mTOR) controls cell fate and responses via its functions in regulating metabolism. Its role in controlling immunity was unraveled by early studies on the immunosuppressive properties of rapamycin. Recent studies have provided insights on how metabolic reprogramming and mTOR signaling impact peripheral T cell activation and fate. The contribution of mTOR and metabolism during early T-cell development in the thymus is also emerging and is the subject of this review. Two major T lineages with distinct immune functions and peripheral homing organs diverge during early thymic development; the αβ- and γδ-T cells, which are defined by their respective TCR subunits. Thymic T-regulatory cells, which have immunosuppressive functions, also develop in the thymus from positively selected αβ-T cells. Here, we review recent findings on how the two mTOR protein complexes, mTORC1 and mTORC2, and the signaling molecules involved in the mTOR pathway are involved in thymocyte differentiation. We discuss emerging views on how metabolic remodeling impacts early T cell development and how this can be mediated via mTOR signaling.
Topics: Animals; Humans; Lymphopoiesis; Signal Transduction; T-Lymphocytes; TOR Serine-Threonine Kinases
PubMed: 34068092
DOI: 10.3390/genes12050728 -
Hematology. American Society of... Dec 2017Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in over a decade ago... (Review)
Review
Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in over a decade ago heralded a new age for patient care as a consequence of improved diagnosis and the development of therapeutic JAK inhibitors. The more recent identification of mutations in calreticulin brought with it a sense of completeness, with most patients with myeloproliferative neoplasm now having a biological basis for their excessive myeloproliferation. We are also beginning to understand the processes that lead to acquisition of somatic mutations and the factors that influence subsequent clonal expansion and emergence of disease. Extended genomic profiling has established a multitude of additional acquired mutations, particularly prevalent in myelofibrosis, where their presence carries prognostic implications. A major goal is to integrate genetic, clinical, and laboratory features to identify patients who share disease biology and clinical outcome, such that therapies, both existing and novel, can be better targeted.
Topics: Animals; DNA Mutational Analysis; Hematologic Neoplasms; Humans; Janus Kinase 2; Mutation; Myelopoiesis; Myeloproliferative Disorders; Protein Kinase Inhibitors
PubMed: 29222295
DOI: 10.1182/asheducation-2017.1.470 -
Pharmacology & Therapeutics Jun 2019Granulocytes are the major type of phagocytes constituting the front line of innate immune defense against bacterial infection. In adults, granulocytes are derived from... (Review)
Review
Granulocytes are the major type of phagocytes constituting the front line of innate immune defense against bacterial infection. In adults, granulocytes are derived from hematopoietic stem cells in the bone marrow. Alcohol is the most frequently abused substance in human society. Excessive alcohol consumption injures hematopoietic tissue, impairing bone marrow production of granulocytes through disrupting homeostasis of granulopoiesis and the granulopoietic response. Because of the compromised immune defense function, alcohol abusers are susceptible to infectious diseases, particularly septic infection. Alcoholic patients with septic infection and granulocytopenia have an exceedingly high mortality rate. Treatment of serious infection in alcoholic patients with bone marrow inhibition continues to be a major challenge. Excessive alcohol consumption also causes diseases in other organ systems, particularly severe alcoholic hepatitis which is life threatening. Corticosteroids are the only therapeutic option for improving short-term survival in patients with severe alcoholic hepatitis. The existence of advanced alcoholic liver diseases and administration of corticosteroids make it more difficult to treat serious infection in alcoholic patients with the disorder of granulopoieis. This article reviews the recent development in understanding alcohol-induced disruption of marrow granulopoiesis and the granulopoietic response with the focus on progress in delineating cell signaling mechanisms underlying the alcohol-induced injury to hematopoietic tissue. Efforts in exploring effective therapy to improve patient care in this field will also be discussed.
Topics: Agranulocytosis; Alcoholism; Animals; Ethanol; Granulocytes; Hematopoietic Stem Cells; Homeostasis; Humans; Leukopoiesis
PubMed: 30831129
DOI: 10.1016/j.pharmthera.2019.03.001 -
Pharmacological Research Jul 2021Recruitment of innate immune cells and their accumulation in the arterial wall and infarcted myocardium has been recognized as a central feature of atherosclerosis and... (Review)
Review
Recruitment of innate immune cells and their accumulation in the arterial wall and infarcted myocardium has been recognized as a central feature of atherosclerosis and cardiac ischemic injury, respectively. In both, steady state and under pathological conditions, majority of these cells have a finite life span and are continuously replenished from haematopoietic stem/progenitor cell pool residing in the bone marrow and extramedullary sites. While having a crucial role in the cardiovascular disease development, proliferation and differentiation of innate immune cells within haematopoietic compartments is greatly affected by the ongoing cardiovascular pathology. In the current review, we summarize key cells, processes and tissue compartments that are involved in myelopoiesis under the steady state, during atherosclerosis development and in myocardial infarction.
Topics: Animals; Atherosclerosis; Bone Marrow; Cardiovascular Diseases; Hematopoiesis, Extramedullary; Humans; Myeloid Cells; Myelopoiesis
PubMed: 33979688
DOI: 10.1016/j.phrs.2021.105663 -
Immunological Reviews May 2019Studies over the last decade uncovered overlapping niches for hematopoietic stem cells (HSCs), multipotent progenitor cells, common lymphoid progenitors, and early B... (Review)
Review
Studies over the last decade uncovered overlapping niches for hematopoietic stem cells (HSCs), multipotent progenitor cells, common lymphoid progenitors, and early B cell progenitors. HSC and lymphoid niches are predominantly composed by mesenchymal progenitor cells (MPCs) and by a small subset of endothelial cells. Niche cells create specialized microenvironments through the concomitant production of short-range acting cell-fate determining cytokines such as interleukin (IL)-7 and stem cell factor and the potent chemoattractant C-X-C motif chemokine ligand 12. This type of cellular organization allows for the cross-talk between hematopoietic stem and progenitor cells with niche cells, such that niche cell activity can be regulated by the quality and quantity of hematopoietic progenitors being produced. For example, preleukemic B cell progenitors and preB acute lymphoblastic leukemias interact directly with MPCs, and downregulate IL-7 expression and the production of non-leukemic lymphoid cells. In this review, we discuss a novel model of B cell development that is centered on cellular circuits formed between B cell progenitors and lymphopoietic niches.
Topics: Animals; B-Lymphocytes; Cell Differentiation; Cellular Microenvironment; Chemokine CXCL12; Endothelial Cells; Hematopoietic Stem Cells; Humans; Interleukin-7; Lymphopoiesis; Mesenchymal Stem Cells; Stem Cell Niche
PubMed: 30977190
DOI: 10.1111/imr.12749 -
Cellular & Molecular Immunology Apr 2021Immune homeostasis is maintained by an adequate balance of myeloid and lymphoid responses. In chronic inflammatory states, including cancer, this balance is lost due to... (Review)
Review
Immune homeostasis is maintained by an adequate balance of myeloid and lymphoid responses. In chronic inflammatory states, including cancer, this balance is lost due to dramatic expansion of myeloid progenitors that fail to mature to functional inflammatory neutrophils, macrophages, and dendritic cells (DCs), thus giving rise to a decline in the antitumor effector lymphoid response. Cancer-related inflammation orchestrates the production of hematopoietic growth factors and cytokines that perpetuate recruitment and activation of myeloid precursors, resulting in unresolved and chronic inflammation. This pathologic inflammation creates profound alterations in the intrinsic cellular metabolism of the myeloid progenitor pool, which is amplified by competition for essential nutrients and by hypoxia-induced metabolic rewiring at the tumor site. Therefore, persistent myelopoiesis and metabolic dysfunctions contribute to the development of cancer, as well as to the severity of a broad range of diseases, including metabolic syndrome and autoimmune and infectious diseases. The aims of this review are to (1) define the metabolic networks implicated in aberrant myelopoiesis observed in cancer patients, (2) discuss the mechanisms underlying these clinical manifestations and the impact of metabolic perturbations on clinical outcomes, and (3) explore new biomarkers and therapeutic strategies to restore immunometabolism and differentiation of myeloid cells towards an effector phenotype to increase host antitumor immunity. We propose that the profound metabolic alterations and associated transcriptional changes triggered by chronic and overactivated immune responses in myeloid cells represent critical factors influencing the balance between therapeutic efficacy and immune-related adverse effects (irAEs) for current therapeutic strategies, including immune checkpoint inhibitor (ICI) therapy.
Topics: Animals; Cell Differentiation; Humans; Immunotherapy; Metabolic Networks and Pathways; Myeloid Cells; Myelopoiesis; Neoplasms
PubMed: 33077904
DOI: 10.1038/s41423-020-00556-w -
PERK reprograms hematopoietic progenitor cells to direct tumor-promoting myelopoiesis in the spleen.The Journal of Experimental Medicine Apr 2022The spleen is an important site of hematopoietic stem/progenitor cell (HSPC) preconditioning and tumor-promoting myeloid cell generation in cancer, but the regulatory...
The spleen is an important site of hematopoietic stem/progenitor cell (HSPC) preconditioning and tumor-promoting myeloid cell generation in cancer, but the regulatory mechanism remains unclear. Here, we found that PKR-like endoplasmic reticulum kinase (PERK) mediated HSPC reprogramming into committed MDSC precursors in the spleen via PERK-ATF4-C/EBPβ signaling. Pharmacological and genetic inhibition of this pathway in murine and human HSPCs prevented their myeloid descendant cells from becoming MDSCs even with subsequent exposure to tumor microenvironment (TME) factors. In mice, the selective delivery of PERK antagonists to the spleen was not only sufficient but more effective than the tumor-targeted strategy in preventing MDSC activation in the tumor, leading to profound TME reshaping and tumor regression. Clinically, HSPCs in the spleen of cancer patients exhibit increased PERK signaling correlated with enhanced myelopoiesis. Our findings indicate that PERK-mediated HSPC preconditioning plays a crucial role in MDSC generation, suggesting novel spleen-targeting therapeutic opportunities for restraining the tumor-promoting myeloid response at its source.
Topics: Animals; Endoplasmic Reticulum; Hematopoietic Stem Cells; Humans; Mice; Myelopoiesis; Neoplasms; Pyruvate Kinase; Spleen; Tumor Microenvironment; eIF-2 Kinase
PubMed: 35266960
DOI: 10.1084/jem.20211498 -
Nature Reviews. Immunology Mar 2020Genetic defects that accumulate in haematopoietic stem cells (HSCs) are thought to be responsible for age-related changes in haematopoiesis that include a decline in... (Review)
Review
Genetic defects that accumulate in haematopoietic stem cells (HSCs) are thought to be responsible for age-related changes in haematopoiesis that include a decline in lymphopoiesis and skewing towards the myeloid lineage. This HSC-centric view is based largely on studies showing that HSCs from aged mice exhibit these lineage biases following transplantation into irradiated young recipient mice. In this Opinion article, we make the case that the reliance on this approach has led to inaccurate conclusions regarding the effects of ageing on blood-forming stem cells; we suggest instead that changes in the environment contribute to haematopoietic system ageing. We propose that a complete understanding of how ageing affects haematopoiesis depends on the analysis of blood cell production in unperturbed mice. We describe how this can be achieved using in situ fate mapping. This approach indicates that changes in downstream progenitors, in addition to any HSC defects, may explain the reduced lymphopoiesis and sustained myelopoiesis that occur during ageing.
Topics: Aging; Animals; Cell Differentiation; Cell Lineage; Cellular Senescence; Hematopoiesis; Hematopoietic Stem Cells; Humans; Myelopoiesis
PubMed: 31740804
DOI: 10.1038/s41577-019-0236-2