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Cell Jun 2022Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system (CNS). Bone marrow hematopoietic stem and progenitor cells (HSPCs) rapidly...
Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system (CNS). Bone marrow hematopoietic stem and progenitor cells (HSPCs) rapidly sense immune activation, yet their potential interplay with autoreactive T cells in MS is unknown. Here, we report that bone marrow HSPCs are skewed toward myeloid lineage concomitant with the clonal expansion of T cells in MS patients. Lineage tracing in experimental autoimmune encephalomyelitis, a mouse model of MS, reveals remarkable bone marrow myelopoiesis with an augmented output of neutrophils and Ly6C monocytes that invade the CNS. We found that myelin-reactive T cells preferentially migrate into the bone marrow compartment in a CXCR4-dependent manner. This aberrant bone marrow myelopoiesis involves the CCL5-CCR5 axis and augments CNS inflammation and demyelination. Our study suggests that targeting the bone marrow niche presents an avenue to treat MS and other autoimmune disorders.
Topics: Animals; Bone Marrow; Encephalomyelitis, Autoimmune, Experimental; Hematopoiesis; Humans; Mice; Mice, Inbred C57BL; Multiple Sclerosis
PubMed: 35709748
DOI: 10.1016/j.cell.2022.05.020 -
Annual Review of Immunology Apr 2021Dendritic cells (DCs) possess the ability to integrate information about their environment and communicate it to other leukocytes, shaping adaptive and innate immunity....
Dendritic cells (DCs) possess the ability to integrate information about their environment and communicate it to other leukocytes, shaping adaptive and innate immunity. Over the years, a variety of cell types have been called DCs on the basis of phenotypic and functional attributes. Here, we refocus attention on conventional DCs (cDCs), a discrete cell lineage by ontogenetic and gene expression criteria that best corresponds to the cells originally described in the 1970s. We summarize current knowledge of mouse and human cDC subsets and describe their hematopoietic development and their phenotypic and functional attributes. We hope that our effort to review the basic features of cDC biology and distinguish cDCs from related cell types brings to the fore the remarkable properties of this cell type while shedding some light on the seemingly inordinate complexity of the DC field.
Topics: Animals; Cell Lineage; Dendritic Cells; Humans; Immunity, Innate; Mice
PubMed: 33481643
DOI: 10.1146/annurev-immunol-061020-053707 -
Protein & Cell Mar 2021TET2, a member of ten-eleven translocation (TET) family as α-ketoglutarate- and Fe-dependent dioxygenase catalyzing the iterative oxidation of 5-methylcytosine (5mC),... (Review)
Review
TET2, a member of ten-eleven translocation (TET) family as α-ketoglutarate- and Fe-dependent dioxygenase catalyzing the iterative oxidation of 5-methylcytosine (5mC), has been widely recognized to be an important regulator for normal hematopoiesis especially myelopoiesis. Mutation and dysregulation of TET2 contribute to the development of multiple hematological malignancies. Recent studies reveal that TET2 also plays an important role in innate immune homeostasis by promoting DNA demethylation or independent of its enzymatic activity. Here, we focus on the functions of TET2 in the initiation and resolution of inflammation through epigenetic regulation and signaling network. In addition, we highlight regulation of TET2 at various molecular levels as well as the correlated inflammatory diseases, which will provide the insight to intervene in the pathological process caused by TET2 dysregulation.
Topics: 5-Methylcytosine; Animals; DNA-Binding Proteins; Dioxygenases; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Hematologic Neoplasms; Humans; Immunity, Innate; Inflammation; Proto-Oncogene Proteins; Signal Transduction
PubMed: 33085059
DOI: 10.1007/s13238-020-00796-6 -
Cell May 2022Bone marrow (BM)-mediated trained innate immunity (TII) is a state of heightened immune responsiveness of hematopoietic stem and progenitor cells (HSPC) and their...
Bone marrow (BM)-mediated trained innate immunity (TII) is a state of heightened immune responsiveness of hematopoietic stem and progenitor cells (HSPC) and their myeloid progeny. We show here that maladaptive BM-mediated TII underlies inflammatory comorbidities, as exemplified by the periodontitis-arthritis axis. Experimental-periodontitis-related systemic inflammation in mice induced epigenetic rewiring of HSPC and led to sustained enhancement of production of myeloid cells with increased inflammatory preparedness. The periodontitis-induced trained phenotype was transmissible by BM transplantation to naive recipients, which exhibited increased inflammatory responsiveness and disease severity when subjected to inflammatory arthritis. IL-1 signaling in HSPC was essential for their maladaptive training by periodontitis. Therefore, maladaptive innate immune training of myelopoiesis underlies inflammatory comorbidities and may be pharmacologically targeted to treat them via a holistic approach.
Topics: Animals; Arthritis; Hematopoietic Stem Cells; Immunity, Innate; Mice; Myelopoiesis; Periodontitis
PubMed: 35483374
DOI: 10.1016/j.cell.2022.03.043 -
Cell Sep 2020Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure....
Coronavirus disease 2019 (COVID-19) is a mild to moderate respiratory tract infection, however, a subset of patients progress to severe disease and respiratory failure. The mechanism of protective immunity in mild forms and the pathogenesis of severe COVID-19 associated with increased neutrophil counts and dysregulated immune responses remain unclear. In a dual-center, two-cohort study, we combined single-cell RNA-sequencing and single-cell proteomics of whole-blood and peripheral-blood mononuclear cells to determine changes in immune cell composition and activation in mild versus severe COVID-19 (242 samples from 109 individuals) over time. HLA-DRCD11c inflammatory monocytes with an interferon-stimulated gene signature were elevated in mild COVID-19. Severe COVID-19 was marked by occurrence of neutrophil precursors, as evidence of emergency myelopoiesis, dysfunctional mature neutrophils, and HLA-DR monocytes. Our study provides detailed insights into the systemic immune response to SARS-CoV-2 infection and reveals profound alterations in the myeloid cell compartment associated with severe COVID-19.
Topics: Adult; Aged; CD11 Antigens; COVID-19; Cells, Cultured; Coronavirus Infections; Female; HLA-DR Antigens; Humans; Male; Middle Aged; Myeloid Cells; Myelopoiesis; Pandemics; Pneumonia, Viral; Proteome; Proteomics; Single-Cell Analysis
PubMed: 32810438
DOI: 10.1016/j.cell.2020.08.001 -
Cellular & Molecular Immunology Jan 2020Tumor-promoting inflammation and the avoidance of immune destruction are hallmarks of cancer. While innate immune cells, such as neutrophils, monocytes, and macrophages,... (Review)
Review
Tumor-promoting inflammation and the avoidance of immune destruction are hallmarks of cancer. While innate immune cells, such as neutrophils, monocytes, and macrophages, are critical mediators for sterile and nonsterile inflammation, persistent inflammation, such as that which occurs in cancer, is known to disturb normal myelopoiesis. This disturbance leads to the generation of immunosuppressive myeloid cells, such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Due to their potent suppressive activities against effector lymphocytes and their abundance in the tumor microenvironment, immunosuppressive myeloid cells act as a major barrier to cancer immunotherapy. Indeed, various therapeutic approaches directed toward immunosuppressive myeloid cells are actively being tested in preclinical and clinical studies. These include anti-inflammatory agents, therapeutic blockade of the mobilization and survival of myeloid cells, and immunostimulatory adjuvants. More recently, immune checkpoint molecules expressed on tumor-infiltrating myeloid cells have emerged as potential therapeutic targets to redirect these cells to eliminate tumor cells. In this review, we discuss the complex crosstalk between cancer-related inflammation and immunosuppressive myeloid cells and possible therapeutic strategies to harness antitumor immune responses.
Topics: Animals; Humans; Immune Checkpoint Inhibitors; Immune Tolerance; Macrophages; Myeloid-Derived Suppressor Cells; Myelopoiesis; Neoplasms; Tumor Microenvironment
PubMed: 31611651
DOI: 10.1038/s41423-019-0306-1 -
Immunological Reviews Mar 2023The principle of trained immunity represents innate immune memory due to sustained, mainly epigenetic, changes triggered by endogenous or exogenous stimuli in bone... (Review)
Review
The principle of trained immunity represents innate immune memory due to sustained, mainly epigenetic, changes triggered by endogenous or exogenous stimuli in bone marrow (BM) progenitors (central trained immunity) and their innate immune cell progeny, thereby triggering elevated responsiveness against secondary stimuli. BM progenitors can respond to microbial and sterile signals, thereby possibly acquiring trained immunity-mediated long-lasting alterations that may shape the fate and function of their progeny, for example, neutrophils. Neutrophils, the most abundant innate immune cell population, are produced in the BM from committed progenitor cells in a process designated granulopoiesis. Neutrophils are the first responders against infectious or inflammatory challenges and have versatile functions in immunity. Together with other innate immune cells, neutrophils are effectors of peripheral trained immunity. However, given the short lifetime of neutrophils, their ability to acquire immunological memory may lie in the central training of their BM progenitors resulting in generation of reprogrammed, that is, "trained", neutrophils. Although trained immunity may have beneficial effects in infection or cancer, it may also mediate detrimental outcomes in chronic inflammation. Here, we review the emerging research area of trained immunity with a particular emphasis on the role of neutrophils and granulopoiesis.
Topics: Humans; Neutrophils; Immunity, Innate; Trained Immunity; Inflammation; Bone Marrow
PubMed: 36190144
DOI: 10.1111/imr.13142 -
Frontiers in Immunology 2019Circulating monocytes can infiltrate mucosal or inflamed tissues where they differentiate into either macrophages or dendritic cells. This paradigm is supported by... (Review)
Review
Circulating monocytes can infiltrate mucosal or inflamed tissues where they differentiate into either macrophages or dendritic cells. This paradigm is supported by numerous studies conducted in mice and in different settings for human cells. Determining whether it holds true in humans is essential for the successful design of monocyte-targeting therapies. Despite limitations inherent to working with human samples, there is accumulating evidence of the existence of generated monocyte-derived cells in humans. Here, we review recent studies showing the recruitment of human monocytes into tissues and their differentiation into macrophages or dendritic cells, in normal or pathological settings. We examine the methods available in human studies to demonstrate the monocytic origin of infiltrating cells. Finally, we review the functions of human monocyte-derived cells and how they might contribute to pathogeny.
Topics: Animals; Dendritic Cells; Humans; Macrophages; Monocytes; Myelopoiesis
PubMed: 31456804
DOI: 10.3389/fimmu.2019.01907 -
Blood Jul 2020Our understanding of the genetics of acute myeloid leukemia (AML) development from myelodysplastic syndrome (MDS) has advanced significantly as a result of... (Review)
Review
Our understanding of the genetics of acute myeloid leukemia (AML) development from myelodysplastic syndrome (MDS) has advanced significantly as a result of next-generation sequencing technology. Although differences in cell biology and maturation exist between MDS and AML secondary to MDS, these 2 diseases are genetically related. MDS and secondary AML cells harbor mutations in many of the same genes and functional categories, including chromatin modification, DNA methylation, RNA splicing, cohesin complex, transcription factors, cell signaling, and DNA damage, confirming that they are a disease continuum. Differences in the frequency of mutated genes in MDS and secondary AML indicate that the order of mutation acquisition is not random during progression. In almost every case, disease progression is associated with clonal evolution, typically defined by the expansion or emergence of a subclone with a unique set of mutations. Monitoring tumor burden and clonal evolution using sequencing provides advantages over using the blast count, which underestimates tumor burden, and could allow for early detection of disease progression prior to clinical deterioration. In this review, we outline advances in the study of MDS to secondary AML progression, with a focus on the genetics of progression, and discuss the advantages of incorporating molecular genetic data in the diagnosis, classification, and monitoring of MDS to secondary AML progression. Because sequencing is becoming routine in the clinic, ongoing research is needed to define the optimal assay to use in different clinical situations and how the data can be used to improve outcomes for patients with MDS and secondary AML.
Topics: Cell Count; Clonal Evolution; DNA Methylation; DNA Mutational Analysis; Disease Progression; Epigenesis, Genetic; Hematopoietic Stem Cells; Humans; Lenalidomide; Leukemia, Myeloid, Acute; Mutation; Myelodysplastic Syndromes; Myelopoiesis; Neoplastic Stem Cells; Prognosis; Tumor Burden; Exome Sequencing; Whole Genome Sequencing
PubMed: 32430504
DOI: 10.1182/blood.2019000942 -
Cell Stem Cell Oct 2021It is critical to understand how human quiescent long-term hematopoietic stem cells (LT-HSCs) sense demand from daily and stress-mediated cues and then transition into...
It is critical to understand how human quiescent long-term hematopoietic stem cells (LT-HSCs) sense demand from daily and stress-mediated cues and then transition into bioenergetically active progeny to differentiate and meet these cellular needs. However, the demand-adapted regulatory circuits of these early steps of hematopoiesis are largely unknown. Here we show that lysosomes, sophisticated nutrient-sensing and signaling centers, are regulated dichotomously by transcription factor EB (TFEB) and MYC to balance catabolic and anabolic processes required for activating LT-HSCs and guiding their lineage fate. TFEB-mediated induction of the endolysosomal pathway causes membrane receptor degradation, limiting LT-HSC metabolic and mitogenic activation, promoting quiescence and self-renewal, and governing erythroid-myeloid commitment. In contrast, MYC engages biosynthetic processes while repressing lysosomal catabolism, driving LT-HSC activation. Our study identifies TFEB-mediated control of lysosomal activity as a central regulatory hub for proper and coordinated stem cell fate determination.
Topics: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cell Differentiation; Hematopoiesis; Hematopoietic Stem Cells; Humans; Lysosomes; Signal Transduction
PubMed: 34343492
DOI: 10.1016/j.stem.2021.07.003