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Frontiers in Immunology 2021B cells are central to the pathogenesis of multiple autoimmune diseases, through antigen presentation, cytokine secretion, and the production of autoantibodies. During... (Review)
Review
B cells are central to the pathogenesis of multiple autoimmune diseases, through antigen presentation, cytokine secretion, and the production of autoantibodies. During development and differentiation, B cells undergo drastic changes in their physiology. It is emerging that these are accompanied by equally significant shifts in metabolic phenotype, which may themselves also drive and enforce the functional properties of the cell. The dysfunction of B cells during autoimmunity is characterised by the breaching of tolerogenic checkpoints, and there is developing evidence that the metabolic state of B cells may contribute to this. Determining the metabolic phenotype of B cells in autoimmunity is an area of active study, and is important because intervention by metabolism-altering therapeutic approaches may represent an attractive treatment target.
Topics: Autoimmune Diseases; Autoimmunity; Autophagy; B-Lymphocytes; Biomarkers; Disease Susceptibility; Energy Metabolism; Humans; Lymphocyte Activation; Lymphopoiesis; Molecular Targeted Therapy
PubMed: 34163480
DOI: 10.3389/fimmu.2021.681105 -
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 -
Cell Metabolism Aug 2022Exercise can prevent osteoporosis and improve immune function, but the mechanism remains unclear. Here, we show that exercise promotes reticulocalbin-2 secretion from...
Exercise can prevent osteoporosis and improve immune function, but the mechanism remains unclear. Here, we show that exercise promotes reticulocalbin-2 secretion from the bone marrow macrophages to initiate bone marrow fat lipolysis. Given the crucial role of lipolysis in exercise-stimulated osteogenesis and lymphopoiesis, these findings suggest that reticulocalbin-2 is a pivotal regulator of a local adipose-osteogenic/immune axis. Mechanistically, reticulocalbin-2 binds to a functional receptor complex, which is composed of neuronilin-2 and integrin beta-1, to activate a cAMP-PKA signaling pathway that mobilizes bone marrow fat via lipolysis to fuel the differentiation and function of mesenchymal and hematopoietic stem cells. Notably, the administration of recombinant reticulocalbin-2 in tail-suspended and old mice remarkably decreases bone marrow fat accumulation and promotes osteogenesis and lymphopoiesis. These findings identify reticulocalbin-2 as a novel mechanosensitive lipolytic factor in maintaining energy homeostasis in bone resident cells, and it provides a promising target for skeletal and immune health.
Topics: Animals; Bone Marrow; Bone Marrow Cells; Cell Differentiation; Cells, Cultured; Lipolysis; Lymphopoiesis; Mesenchymal Stem Cells; Mice; Osteogenesis
PubMed: 35705079
DOI: 10.1016/j.cmet.2022.05.009 -
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 -
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 Feb 2020Immune responses in diverse tissue sites are critical for protective immunity and homeostasis. Here, we investigate how tissue localization regulates the development and...
Immune responses in diverse tissue sites are critical for protective immunity and homeostasis. Here, we investigate how tissue localization regulates the development and function of human natural killer (NK) cells, innate lymphocytes important for anti-viral and tumor immunity. Integrating high-dimensional analysis of NK cells from blood, lymphoid organs, and mucosal tissue sites from 60 individuals, we identify tissue-specific patterns of NK cell subset distribution, maturation, and function maintained across age and between individuals. Mature and terminally differentiated NK cells with enhanced effector function predominate in blood, bone marrow, spleen, and lungs and exhibit shared transcriptional programs across sites. By contrast, precursor and immature NK cells with reduced effector capacity populate lymph nodes and intestines and exhibit tissue-resident signatures and site-specific adaptations. Together, our results reveal anatomic control of NK cell development and maintenance as tissue-resident populations, whereas mature, terminally differentiated subsets mediate immunosurveillance through diverse peripheral sites. VIDEO ABSTRACT.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Antigens, CD; Cells, Cultured; Child; Female; Humans; Immunity, Innate; Intestinal Mucosa; Killer Cells, Natural; Lung; Lymph Nodes; Lymphopoiesis; Male; Middle Aged; Spleen
PubMed: 32059780
DOI: 10.1016/j.cell.2020.01.022 -
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 -
Nature Mar 2021Stromal cells in adult bone marrow that express leptin receptor (LEPR) are a critical source of growth factors, including stem cell factor (SCF), for the maintenance of...
Stromal cells in adult bone marrow that express leptin receptor (LEPR) are a critical source of growth factors, including stem cell factor (SCF), for the maintenance of haematopoietic stem cells and early restricted progenitors. LEPR cells are heterogeneous, including skeletal stem cells and osteogenic and adipogenic progenitors, although few markers have been available to distinguish these subsets or to compare their functions. Here we show that expression of an osteogenic growth factor, osteolectin, distinguishes peri-arteriolar LEPR cells poised to undergo osteogenesis from peri-sinusoidal LEPR cells poised to undergo adipogenesis (but retaining osteogenic potential). Peri-arteriolar LEPRosteolectin cells are rapidly dividing, short-lived osteogenic progenitors that increase in number after fracture and are depleted during ageing. Deletion of Scf from adult osteolectin cells did not affect the maintenance of haematopoietic stem cells or most restricted progenitors but depleted common lymphoid progenitors, impairing lymphopoiesis, bacterial clearance, and survival after acute bacterial infection. Peri-arteriolar osteolectin cell maintenance required mechanical stimulation. Voluntary running increased, whereas hindlimb unloading decreased, the frequencies of peri-arteriolar osteolectin cells and common lymphoid progenitors. Deletion of the mechanosensitive ion channel PIEZO1 from osteolectin cells depleted osteolectin cells and common lymphoid progenitors. These results show that a peri-arteriolar niche for osteogenesis and lymphopoiesis in bone marrow is maintained by mechanical stimulation and depleted during ageing.
Topics: Adipose Tissue; Aging; Animals; Arterioles; Bone Marrow Cells; Bone and Bones; Female; Hematopoietic Cell Growth Factors; Lectins, C-Type; Lymphocytes; Lymphopoiesis; Male; Mice; Osteogenesis; Receptors, Leptin; Stem Cell Factor; Stem Cell Niche; Stromal Cells
PubMed: 33627868
DOI: 10.1038/s41586-021-03298-5 -
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 -
Science (New York, N.Y.) Feb 2022The extension of life span driven by 40% caloric restriction (CR) in rodents causes trade-offs in growth, reproduction, and immune defense that make it difficult to...
The extension of life span driven by 40% caloric restriction (CR) in rodents causes trade-offs in growth, reproduction, and immune defense that make it difficult to identify therapeutically relevant CR-mimetic targets. We report that about 14% CR for 2 years in healthy humans improved thymopoiesis and was correlated with mobilization of intrathymic ectopic lipid. CR-induced transcriptional reprogramming in adipose tissue implicated pathways regulating mitochondrial bioenergetics, anti-inflammatory responses, and longevity. Expression of the gene encoding platelet activating factor acetyl hydrolase (PLA2G7) is inhibited in humans undergoing CR. Deletion of Pla2g7 in mice showed decreased thymic lipoatrophy, protection against age-related inflammation, lowered NLRP3 inflammasome activation, and improved metabolic health. Therefore, the reduction of PLA2G7 may mediate the immunometabolic effects of CR and could potentially be harnessed to lower inflammation and extend the health span.
Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Adipose Tissue; Adult; Aging; Animals; Caloric Restriction; Down-Regulation; Energy Metabolism; Female; Humans; Immune System; Inflammasomes; Inflammation; Longevity; Lymphopoiesis; Macrophages; Male; Mice; Middle Aged; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein; Thermogenesis; Thymus Gland; Transcriptome
PubMed: 35143297
DOI: 10.1126/science.abg7292