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1.
Exercise-associated prevention of adult cardiovascular disease in children and adolescents: monocytes, molecular mechanisms, and a call for discovery.
Cooper, DM, Radom-Aizik, S
Pediatric research. 2020;(2):309-318
Abstract
Atherosclerosis originates in childhood and adolescence. The goal of this review is to highlight how exercise and physical activity during childhood and adolescence, critical periods of growth and development, can prevent adult cardiovascular disease (CVD), particularly through molecular mechanisms of monocytes, a key cell of the innate immune system. Monocytes are heterogeneous and pluripotential cells that can, paradoxically, play a role in both the instigation and prevention of atherosclerosis. Recent discoveries in young adults reveal that brief exercise affects monocyte gene pathways promoting a cell phenotype that patrols the vascular system and repairs injuries. Concurrently, exercise inhibits pro-inflammatory monocytes, cells that contribute to vascular damage and plaque formation. Because CVD is typically asymptomatic in youth, minimally invasive techniques must be honed to study the subtle anatomic and physiologic evidence of vascular dysfunction. Exercise gas exchange and heart rate measures can be combined with ultrasound assessments of vascular anatomy and reactivity, and near-infrared spectroscopy to quantify impaired O2 transport that is often hidden at rest. Combined with functional, transcriptomic, and epigenetic monocyte expression and measures of monocyte-endothelium interaction, molecular mechanisms of early CVD can be formulated, and then translated into effective physical activity-based strategies in youth to prevent adult-onset CVD.
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2.
The vitamin D-dependent transcriptome of human monocytes.
Neme, A, Nurminen, V, Seuter, S, Carlberg, C
The Journal of steroid biochemistry and molecular biology. 2016;:180-187
Abstract
Monocytes are important cells of the innate immune system that can differentiate into macrophages and dendritic cells. The biologically active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), serves as a ligand of the nuclear receptor vitamin D receptor (VDR). A key physiological function of 1,25(OH)2D3 is the defense against pathogens, such as those causing tuberculosis, that involves the modulation of the monocyte transcriptome. THP-1 cells are an established model of human monocytes, for which the at present largest set of 1,25(OH)2D3-affected genome-wide data are available. Here we summarize the insight obtained from the recent transcriptome of 1,25(OH)2D3-stimulated THP-1 cells, that was determined by triplicate RNA sequencing (RNA-seq). Primary and secondary vitamin D target genes being up- and down-regulated were related to changes in the epigenome of THP-1 cells, such as 1,25(OH)2D3-dependent chromatin opening and modulation of the genome-wide association of the transcription factors VDR and CCCTC-binding factor (CTCF) with their respective genomic binding sites. The anti-microbial response is the top-ranking early physiological function represented by 1,25(OH)2D3-stimulated genomic regions and genes, but also other immunity-related pathways, such as IL10 signaling, are activated. Taken together, the epigenomic and transcriptomic responses of THP-1 cells to 1,25(OH)2D3 represent a master example of the impact of vitamin D on human physiology.
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3.
Role of the immune system in HIV-associated neuroinflammation and neurocognitive implications.
Hong, S, Banks, WA
Brain, behavior, and immunity. 2015;:1-12
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Abstract
Individuals living with HIV who are optimally treated with combination antiretroviral therapy (cART) can now lead an extended life. In spite of this remarkable survival benefit from viral suppression achieved by cART in peripheral blood, the rate of mild to moderate cognitive impairment remains high. A cognitive decline that includes impairments in attention, learning and executive function is accompanied by increased rates of mood disorders that together adversely impact the daily life of those with chronic HIV infection. The evidence is clear that cells in the brain are infected with HIV that has crossed the blood-brain barrier both as cell-free virus and within infected monocytes and T cells. Viral proteins that circulate in blood can induce brain endothelial cells to release cytokines, invoking another source of neuroinflammation. The difficulty of efficient delivery of cART to the central nervous system (CNS) contributes to elevated viral load in the CNS, resulting in a persistent HIV-associated neurocognitive disorders (HAND). The pathogenesis of HAND is multifaceted, and mounting evidence indicates that immune cells play a major role. HIV-infected monocytes and T cells not only infect brain resident cells upon migration into the CNS but also produce proinflammatory cytokines such as TNF and IL-1ß, which in turn, further activate microglia and astrocytes. These activated brain resident cells, along with perivascular macrophages, are the main contributors to neuroinflammation in HIV infection and release neurotoxic factors such as excitatory amino acids and inflammatory mediators, resulting in neuronal dysfunction and death. Cytokines, which are elevated in the blood of patients with HIV infection, may also contribute to brain inflammation by entering the brain from the blood. Host factors such as aging and co-morbid conditions such as cytomegalovirus co-infection and vascular pathology are important factors that affect the HIV-host immune interactions in HAND pathogenesis. By these diverse mechanisms, HIV-1 induces a neuroinflammatory response that is likely to be a major contributor to the cognitive and behavior changes seen in HIV infection.
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4.
THP-1 cell line: an in vitro cell model for immune modulation approach.
Chanput, W, Mes, JJ, Wichers, HJ
International immunopharmacology. 2014;(1):37-45
Abstract
THP-1 is a human leukemia monocytic cell line, which has been extensively used to study monocyte/macrophage functions, mechanisms, signaling pathways, and nutrient and drug transport. This cell line has become a common model to estimate modulation of monocyte and macrophage activities. This review attempts to summarize and discuss recent publications related to the THP-1 cell model. An overview on the biological similarities and dissimilarities between the THP-1 cell line and human peripheral blood mononuclear cell (PBMC) derived-monocytes and macrophages, as well as the advantages and disadvantages of the use of THP-1 cell line, is included. The review summarizes different published co-cultivation studies of THP-1 cells with other cell types, for instance, intestinal cells, adipocytes, T-lymphocytes, platelets, and vascular smooth muscle cells, which can be an option to study cell-cell interaction in vitro and can be an approach to better mimic in vivo conditions. Macrophage polarization is a relatively new topic which gains interest for which the THP-1 cell line also may be relevant. Besides that an overview of newly released commercial THP-1 engineered-reporter cells and THP-1 inflammasome test-cells is also given. Evaluation of recent papers leads to the conclusion that the THP-1 cell line has unique characteristics as a model to investigate/estimate immune-modulating effects of compounds in both activated and resting conditions of the cells. Although the THP-1 response can hint to potential responses that might occur ex vivo or in vivo, these should be, however, validated by in vivo studies to draw more definite conclusions.
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5.
Modulation of CD8(+) T-cell activation events by monocytic and granulocytic myeloid-derived suppressor cells.
Schouppe, E, Van Overmeire, E, Laoui, D, Keirsse, J, Van Ginderachter, JA
Immunobiology. 2013;(11):1385-91
Abstract
Myeloid-derived suppressor cells are immature myeloid cells, consisting of a monocytic and a granulocytic fraction, that are known to suppress anti-tumor immune responses. Important targets of the immunosuppressive capacity of MDSC are CD8(+) T cells, which are crucial cytotoxic effector cells in immunotherapeutic settings. CD8(+) T-cell activation and differentiation comprises a well-orchestrated series of events, starting from early TCR-mediated signaling and leading to cytokine secretion, the expression of activation markers, proliferation and the differentiation into several subsets of effector and memory cells. In this review, we summarize the available data on how the production of reactive oxygen species, nitric oxide, the arginase-mediated depletion of l-arginine and Cystine depletion by MDSCs interfere with the signaling molecules necessary for normal CTL differentiation and activation.
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6.
The role of immune-related myeloid cells in angiogenesis.
Chambers, SE, O'Neill, CL, O'Doherty, TM, Medina, RJ, Stitt, AW
Immunobiology. 2013;(11):1370-5
Abstract
Macrophage function is not restricted to the innate and adaptive immune responses, but also includes host defence, wound healing, angiogenesis and homeostatic processes. Within the spectrum of macrophage activation there are two extremes: M1 classically activated macrophages which have a pro-inflammatory phenotype, and M2 alternatively activated macrophages which are pro-angiogenic and anti-inflammatory. An important property of macrophages is their plasticity to switch from one phenotype to the other and they can be defined in their polarisation state at any point between the two extremes. In order to determine what stage of activation macrophages are in, it is essential to profile various phenotypic markers for their identification. This review describes the angiogenic role for myeloid cells: circulating monocytes, Tie-2 expressing monocytes (TEMs), myeloid-derived suppressor cells (MDSCs), tumour associated macrophages (TAMs), and neutrophils. Each cell type is discussed by phenotype, roles within angiogenesis and possible targets as a cell therapy. In addition, we also refer to our own research on myeloid angiogenic cells (MACs), outlining their ability to induce angiogenesis and their similarities to alternatively activated M2 macrophages. MACs significantly contribute to vascular repair through paracrine mechanisms as they lack the capacity to differentiate into endothelial cells. Since MACs also retain plasticity, phenotypic changes can occur according to disease states and the surrounding microenvironment. This pro-angiogenic potential of MACs could be harnessed as a novel cellular therapy for the treatment of ischaemic diseases, such as diabetic retinopathy, hind limb ischaemia and myocardial infarction; however, caution needs to be taken when MACs are delivered into an inflammatory milieu.
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7.
Peripheral mononuclear cell rejuvenation for senescence surveillance in Alzheimer disease.
Malavolta, M, Basso, A, Piacenza, F, Costarelli, L, Giacconi, R, Mocchegiani, E
Current pharmaceutical design. 2013;(9):1720-6
Abstract
Recent observations have pointed out that microglia, astrocytes and cerebrovascular endothelial cells senescence might contribute to the onset or progression of sporadic AD. The accumulation of senescent dysfunctional microglia or senescence related changes of other cells within CNS could be causally implicated in AD and age-related dysfunction and their efficient removal could represent a pivotal mechanism to prevent or delay neurodegeneration. The question how senescent cells are cleared from CNS has been poorly investigated, even though it is reasonable to believe that resident microglia is involved in this task. However, accumulating evidence now support the idea that assistance by peripheral mononuclear phagocytes (MP) in AD could be essential to control local brain inflammation and remove Abeta depots. Based on the current knowledge it is reasonable to hypothesize that senescence surveillance might be among the tasks that blood derived MP are called to envelop in the CNS during particular conditions, especially in the case senescent microglia is not able to achieve this task properly. However, age-related dysfunctions of these players of innate immunity could lead to depict a series of events that synergically with microglia and other CNS cells senescence could lead to a rapid progression of the disease. Hence, the design of intervention aimed at targeting accumulating senescent cells by rejuvenation of peripheral MP function seems an attractive tool that perhaps would also help to clarify the processes involved in senescence surveillance in normal and AD brain.
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8.
Auxin and monocot development.
McSteen, P
Cold Spring Harbor perspectives in biology. 2010;(3):a001479
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Abstract
Monocots are known to respond differently to auxinic herbicides; hence, certain herbicides kill broadleaf (i.e., dicot) weeds while leaving lawns (i.e., monocot grasses) intact. In addition, the characters that distinguish monocots from dicots involve structures whose development is controlled by auxin. However, the molecular mechanisms controlling auxin biosynthesis, homeostasis, transport, and signal transduction appear, so far, to be conserved between monocots and dicots, although there are differences in gene copy number and expression leading to diversification in function. This article provides an update on the conservation and diversification of the roles of genes controlling auxin biosynthesis, transport, and signal transduction in root, shoot, and reproductive development in rice and maize.
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9.
[Roles of PPAR and p21WAF1/CIP1 in monocyte/macrophage differentiation: are circulating monocytes able to proliferate?].
Dubourdeau, M, Pipy, B, Rousseau, D
Medecine sciences : M/S. 2010;(5):481-6
Abstract
Macrophages are involved in the immune and the inflammatory response. The deregulation of their physiological properties is associated with several pathologies such as atherosclerosis and some cancers. Cytokines action on this blood lineage modulates p21WAF1/CIP1 expression. It appears that this protein may play a role in the inflammation regulation through PPAR (peroxysome proliferator-activated receptors) transcription factors, strongly linked to lipid metabolism. It could also be involved in the control of the proliferation of monocytes/macrophages, even if these cells are classically described as devoided of any proliferative capacity.
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10.
Targeting bacterial endotoxin: two sides of a coin.
Bosshart, H, Heinzelmann, M
Annals of the New York Academy of Sciences. 2007;:1-17
Abstract
The term sepsis describes a potentially lethal clinical condition that develops as a result of a dysregulated host response to bacterial infection. The most common bacterial component implicated in initiating the septic syndrome is a cell wall molecule derived from Gram-negative bacteria, known as lipopolysaccharide (LPS) or endotoxin. Like all mammals, humans are equipped with an LPS-sensing machinery consisting, primarily, of LPS-binding protein (LBP), CD14, a glycosylphosphatidylinositol (GPI)-anchored monocyte differentiation antigen, and toll-like receptor 4 (TLR4), a signal-transducing integral membrane protein. Modest stimulation of TLR4 facilitates the elimination of invading microorganisms. Potent TLR4 stimulation, however, produces severe reactions in the host, often leading to multiple organ failure and death. The search for pharmaceuticals that reduce mortality in septic patients has been a painstaking process. Thus far, only a few compounds have been found to significantly reduce mortality rates. Perhaps one of the more promising therapeutic strategies currently pursued is based on the identification of synthetic or naturally occurring substances that neutralize LPS or inhibit LPS-mediated activation of host immune cells, such as monocytes and macrophages. Here, we describe a number of diverse molecular structures with a capacity to either enhance or blunt LPS-induced monocyte activation. The underlying molecular mechanisms are discussed.