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RNA (New York, N.Y.) Jul 2022The poly(A) tail enhances translation and transcript stability, and tail length is under dynamic control during cell state transitions. Tail regulation plays essential...
The poly(A) tail enhances translation and transcript stability, and tail length is under dynamic control during cell state transitions. Tail regulation plays essential roles in translational timing and fertilization in early development, but poly(A) tail dynamics have not been fully explored in post-embryonic systems. Here, we examined the landscape and impact of tail length control during macrophage activation. Upon activation, more than 1500 mRNAs, including proinflammatory genes, underwent distinctive changes in tail lengths. Increases in tail length correlated with mRNA levels regardless of transcriptional activity, and many mRNAs that underwent tail extension encode proteins necessary for immune function and post-transcriptional regulation. Strikingly, we found that , whose protein product destabilizes target transcripts, undergoes tail extension. Our analyses indicate that many mRNAs undergoing tail lengthening are, in turn, degraded by elevated levels of ZFP36, constituting a post-transcriptional feedback loop that ensures transient regulation of transcripts integral to macrophage activation. Taken together, this study establishes the complexity, relevance, and widespread nature of poly(A) tail dynamics, and the resulting post-transcriptional regulation during macrophage activation.
Topics: Gene Expression Regulation; Macrophage Activation; Poly A; Polyadenylation; RNA, Messenger
PubMed: 35512831
DOI: 10.1261/rna.078918.121 -
Cardiovascular Research Jul 2023
Topics: Humans; Macrophages; Atherosclerosis; Macrophage Activation; Plaque, Atherosclerotic
PubMed: 37226046
DOI: 10.1093/cvr/cvad072 -
Small (Weinheim An Der Bergstrasse,... May 2020Toxic effects of certain carbon nanomaterials (CNM) have been observed in several exposure scenarios both in vivo and in vitro. However, most of the data currently...
Toxic effects of certain carbon nanomaterials (CNM) have been observed in several exposure scenarios both in vivo and in vitro. However, most of the data currently available has been generated in a high-dose/acute exposure setup, limiting the understanding of their immunomodulatory mechanisms. Here, macrophage-like THP-1 cells, exposed to ten different CNM for 48 h in low-cytotoxic concentration of 10 µg mL , are characterized by secretion of different cytokines and global transcriptional changes. Subsequently, the relationships between cytokine secretion and transcriptional patterns are modeled, highlighting specific pathways related to alternative macrophage activation. Finally, time- and dose-dependent activation of transcription and secretion of M1 marker genes IL-1β and tumor necrosis factor, and M2 marker genes IL-10 and CSF1 is confirmed among the three most responsive CNM, with concentrations of 5, 10, and 20 µg mL at 24, 48, and 72 h of exposure. These results underline CNM effects on the formation of cell microenvironment and gene expression leading to specific patterns of macrophage polarization. Taken together, these findings imply that, instead of a high and toxic CNM dose, a sub-lethal dose in controlled exposure setup can be utilized to alter the cell microenvironment and program antigen presenting cells, with fascinating implications for novel therapeutic strategies.
Topics: Carbon; Cytokines; Gene Expression Profiling; Gene Expression Regulation; Humans; Macrophage Activation; Macrophages; Nanostructures; THP-1 Cells
PubMed: 32250056
DOI: 10.1002/smll.201907609 -
Molecules (Basel, Switzerland) Mar 2022The discovery of safe and effective plant polysaccharides with immunomodulatory effects has become a research hotspot. Raspberry is an essential commercial fruit and is...
The discovery of safe and effective plant polysaccharides with immunomodulatory effects has become a research hotspot. Raspberry is an essential commercial fruit and is widely distributed, cultivated, and consumed worldwide. In the present study, a homogeneous acidic polysaccharide (RPP-2a), with a weight-average molecular weight (Mw) of 55582 Da, was isolated from the pulp of raspberries through DEAE-Sepharose Fast Flow and Sephadex G-200 chromatography. RPP-2a consisted of rhamnose, arabinose, galactose, glucose, xylose, galacturonic acid and glucuronic acid, with a molar ratio of 15.4:9.6:7.6:3.2:9.1:54.3:0.8. The results of Fourier transform infrared spectroscopy (FT-IR), gas chromatography-mass spectrometer (GC-MS), 1D-, and 2D-nuclear magnetic resonance (NMR) analyses suggested that the backbone of RPP-2a was primarily composed of →2)--L-Rha-(1→, →2,4)--L-Rha-(1→, →4)--D-GalA-(1→, and →3,4)--D-Glc-(1→ sugar moieties, with side chains of -L-Ara-(1→, -L-Ara-(1→, and -D-Gal-(1→3)--D-Gal-(1→ residues linked to the O-4 band of rhamnose and O-3 band of glucose residues. Furthermore, RPP-2a exhibited significant macrophage activation activity by increasing the production of nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and the expression of inducible nitric oxide synthase (iNOS) and cytokines at the transcriptional level in RAW264.7 cells. Overall, the results indicate that RPP-2a can be utilized as a potential natural immune-enhancing agent.
Topics: Animals; Macrophage Activation; Mice; Polysaccharides; RAW 264.7 Cells; Rubus; Spectroscopy, Fourier Transform Infrared
PubMed: 35268775
DOI: 10.3390/molecules27051674 -
Seminars in Immunopathology Sep 2019Emerging evidence suggest that macrophage and osteoclast are two competing differentiation outcomes from myeloid progenitors. In this review, we summarize recent... (Review)
Review
Emerging evidence suggest that macrophage and osteoclast are two competing differentiation outcomes from myeloid progenitors. In this review, we summarize recent advances in the understanding of the molecular mechanisms controlling the polarization of macrophage and osteoclast. These include nuclear receptors/transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ) and estrogen-related receptor α (ERRα), their transcription cofactor PPARγ coactivator 1-β (PGC-1β), metabolic factors such as mitochondrial complex I (CI) component NADH:ubiquinone oxidoreductase iron-sulfur protein 4 (Ndufs4), as well as transmembrane receptors such as very-low-density-lipoprotein receptor (VLDLR). These molecular rheostats promote osteoclast differentiation but suppress proinflammatory macrophage activation and inflammation, by acting lineage-intrinsically, systemically or cross generation. These findings provide new insights to the understanding of the interactions between innate immunity and bone remodeling, advancing the field of osteoimmunology.
Topics: Animals; Biomarkers; Bone and Bones; Humans; Immunomodulation; Macrophage Activation; Macrophages; Osteoclasts; Osteogenesis; Osteoprotegerin; PPAR gamma; RANK Ligand; RNA-Binding Proteins; Receptor Activator of Nuclear Factor-kappa B; Receptors, Estrogen; Receptors, LDL; Signal Transduction; ERRalpha Estrogen-Related Receptor
PubMed: 31506868
DOI: 10.1007/s00281-019-00754-3 -
Nature Immunology Jan 2016In tissues, macrophages are exposed to metabolic, homeostatic and immunoregulatory signals of local or systemic origin that influence their basal functions and responses... (Review)
Review
In tissues, macrophages are exposed to metabolic, homeostatic and immunoregulatory signals of local or systemic origin that influence their basal functions and responses to danger signals. Signal-transduction pathways regulated by extracellular signals are coupled to distinct sets of broadly expressed stimulus-regulated transcription factors whose ability to elicit gene-expression changes is influenced by the accessibility of their binding sites in the macrophage genome. In turn, accessibility of macrophage-specific transcriptional regulatory elements (enhancers and promoters) is specified by transcription factors that determine the macrophage lineage or impose their tissue-specific properties. Here we review recent findings that advance the understanding of mechanisms underlying priming and signal-dependent activation of macrophages and discuss the effect of genetic variation on these processes.
Topics: Animals; Epigenesis, Genetic; Gene Expression Regulation; Humans; Macrophage Activation; Macrophages; Signal Transduction
PubMed: 26681459
DOI: 10.1038/ni.3306 -
Comparison of Macrophage Activation Using γ-Globulin and Serum-derived Macrophage Activating Factor.Anticancer Research Aug 2020Serum-derived macrophage activating factor (serum-MAF) can rapidly activate macrophage phagocytic activity by inducing characteristic membrane ruffles designated as... (Comparative Study)
Comparative Study
BACKGROUND/AIM
Serum-derived macrophage activating factor (serum-MAF) can rapidly activate macrophage phagocytic activity by inducing characteristic membrane ruffles designated as Frill-like structures. Serum-MAF contains γ-globulin, an activator of phagocytosis. This study examined whether serum-MAF and γ-globulin activate macrophages similarly.
MATERIALS AND METHODS
Morphological changes in macrophages were observed by time-lapse imaging and the efficiency of engulfment was analysed quantitatively. Immunological staining of talin-1 and a calpain inhibitor were performed.
RESULTS
The engulfment efficiency of serum-MAF- and γ-globulin-activated macrophages was significantly different. Talin-1 showed weak co-localisation with the Frill-like structures. Treatment with a calpain inhibitor similarly down-regulated phagocytosis irrespective of the activation factor.
CONCLUSION
There was a difference between macrophage activation mechanisms by γ-globulin and serum-MAF. Talin may slightly contribute to serum-MAF activation. It is possible to distinguish between the calpain-dependent fundamental 'mechanism of phagocytosis' and the activating factor-dependent rapid 'activation mechanism'.
Topics: Calpain; Cell Line; Down-Regulation; Humans; Macrophage Activation; Macrophage-Activating Factors; Macrophages; Phagocytosis; THP-1 Cells; gamma-Globulins
PubMed: 32727796
DOI: 10.21873/anticanres.14471 -
Cancer Metastasis Reviews Sep 2018The tumor immune landscape gained considerable interest based on the knowledge that genetic aberrations in cancer cells alone are insufficient for tumor development.... (Review)
Review
The tumor immune landscape gained considerable interest based on the knowledge that genetic aberrations in cancer cells alone are insufficient for tumor development. Macrophages are basically supporting all hallmarks of cancer and owing to their tremendous plasticity they may exert a whole spectrum of anti-tumor and pro-tumor activities. As part of the innate immune response, macrophages are armed to attack tumor cells, alone or in concert with distinct T cell subsets. However, in the tumor microenvironment, they sense nutrient and oxygen gradients, receive multiple signals, and respond to this incoming information with a phenotype shift. Often, their functional output repertoire is shifted to become tumor-supportive. Incoming and outgoing signals are chemically heterogeneous but also comprise lipid mediators. Here, we review the current understanding whereby arachidonate metabolites derived from the cyclooxygenase and lipoxygenase pathways shape the macrophage phenotype in a tumor setting. We discuss these findings in the context of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1) expression and concomitant prostaglandin E (PGE) formation. We elaborate the multiple actions of this lipid in affecting macrophage biology, which are sensors for and generators of this lipid. Moreover, we summarize properties of 5-lipoxygenases (ALOX5) and 15-lipoxygenases (ALOX15, ALOX15B) in macrophages and clarify how these enzymes add to the role of macrophages in a dynamically changing tumor environment. This review will illustrate the potential routes how COX-2/mPGES-1 and ALOX5/-15 in macrophages contribute to the development and progression of a tumor.
Topics: Animals; Arachidonate 15-Lipoxygenase; Arachidonate 5-Lipoxygenase; Dinoprostone; Gene Expression Regulation, Neoplastic; Humans; Lipid Metabolism; Macrophage Activation; Macrophages; Neoplasms; Prostaglandin-E Synthases; Receptors, Prostaglandin E; Tumor Microenvironment
PubMed: 29808459
DOI: 10.1007/s10555-018-9731-3 -
Results and Problems in Cell... 2017Macrophages are the initial biologic responders to biomaterials. These highly plastic immune sentinels control and modulate responses to materials, foreign or natural.... (Review)
Review
Macrophages are the initial biologic responders to biomaterials. These highly plastic immune sentinels control and modulate responses to materials, foreign or natural. The responses may vary from immune stimulatory to immune suppressive. Several parameters have been identified that influence macrophage response to biomaterials, specifically size, geometry, surface topography, hydrophobicity, surface chemistry, material mechanics, and protein adsorption. In this review, the influence of these parameters is supported with examples of both synthetic and naturally derived materials and illustrates that a combination of these parameters ultimately influences macrophage responses to the biomaterial. Having an understanding of these properties may lead to highly efficient design of biomaterials with desirable biologic response properties.
Topics: Animals; Biocompatible Materials; Humans; Macrophage Activation; Macrophages
PubMed: 28455715
DOI: 10.1007/978-3-319-54090-0_13 -
Journal of Leukocyte Biology Aug 2019The tricarboxylic acid (TCA) cycle is a mitochondrial metabolic hub that coordinates the metabolism of carbohydrates, proteins, and fats into carbon dioxide and ATP. At... (Review)
Review
The tricarboxylic acid (TCA) cycle is a mitochondrial metabolic hub that coordinates the metabolism of carbohydrates, proteins, and fats into carbon dioxide and ATP. At specific points in the cycle, the diversion, import, or export of TCA metabolites allows for the dynamic regulation of a variety of tissue and/or cell-specific phenotypic processes. Recent studies have identified that a number of TCA metabolites are important in controlling monocyte/macrophage phenotypes and effector functions while specific macrophage activation or polarization states functionally determine the relative utilization of each. This review focuses on the metabolic reprogramming of the TCA cycle in macrophages and how individual metabolites play a variety of context-specific roles in determining physiologic and pathologic macrophage activation and homeostatic functions. We discuss the implications of these findings and address unanswered questions regarding the role of the TCA cycle in guiding macrophage-dependent immune responses.
Topics: Animals; Biomarkers; Cellular Reprogramming; Citric Acid Cycle; Energy Metabolism; Humans; Macrophage Activation; Macrophages; Mitochondria; Phenotype
PubMed: 30768807
DOI: 10.1002/JLB.3RU1218-496R