scholarly journals Epigenetic Control of Macrophage Polarisation and Soluble Mediator Gene Expression during Inflammation

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Theodore S. Kapellos ◽  
Asif J. Iqbal
Keyword(s):  
Posttranslational Modifications ◽  
Macrophage Activation ◽  
M1 Macrophages ◽  
Host Environment ◽  
Macrophage Polarisation ◽  
Epigenetic Control ◽  
The Past ◽  
Cytokines And Chemokines ◽  
Soluble Mediator ◽  
Macrophage Phenotypes

Macrophages function as sentinel cells, which constantly monitor the host environment for infection or injury. Macrophages have been shown to exhibit a spectrum of activated phenotypes, which can often be categorised under the M1/M2 paradigm. M1 macrophages secrete proinflammatory cytokines and chemokines, such as TNF-α, IL-6, IL-12, CCL4, and CXCL10, and induce phagocytosis and oxidative dependent killing mechanisms. In contrast, M2 macrophages support wound healing and resolution of inflammation. In the past decade, interest has grown in understanding the mechanisms involved in regulating macrophage activation. In particular, epigenetic control of M1 or M2 activation states has been shown to rely on posttranslational modifications of histone proteins adjacent to inflammatory-related genes. Changes in methylation and acetylation of histones by methyltransferases, demethylases, acetyltransferases, and deacetylases can all impact how macrophage phenotypes are generated. In this review, we summarise the latest advances in the field of epigenetic regulation of macrophage polarisation to M1 or M2 states, with particular focus on the cytokine and chemokine profiles associated with these phenotypes.

Abstract 520: High-density Lipoprotein Inhibits Human M1 Macrophage Polarisation through the Redistribution of Caveolin-1

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Man K Lee ◽  
Xiao-Lei Moore ◽  
Yi Fu ◽  
Annas Al-sharea ◽  
Dragana Dragoljeic ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cholesterol Efflux ◽  
Human Macrophage ◽  
Ros Production ◽  
Oxygen Species ◽  
M1 Macrophages ◽  
Macrophage Polarisation ◽  
Caveolin 1 ◽  
M1 Phenotype ◽  
M2 Phenotype

Macrophages play a critical role in the development and progression of atherosclerosis. Depending on their surrounding milieu, macrophages can adopt a wide range of functional phenotypes; pro-inflammatory (M1) and pro-resolving (M2). HDL has many cardio-protective properties including potent anti-inflammatory effects, largely through the removal of cholesterol from cells. It is currently not known if this extends to influencing human macrophage phenotypes. Thus, we aimed to investigate the effect of HDL on human macrophage polarisation. Human blood monocyte-derived macrophages were induced to either an M1-phenotype by incubation with LPS and IFN-γ or to an M2-phenotype with IL-4. Macrophages were differentiated in the presence or absence of human HDL and their phenotypes were characterised using cell surface markers, reactive oxygen species (ROS) production by flow cytometry, and mRNA expression by real-time PCR. Downstream signalling pathways were also explored. We discovered that HDL inhibited the induction to M1 as evidenced by a decrease in cell surface marker expression; CD192 and CD64. This was accompanied by a decreased expression of M1-associated inflammatory genes TNF-α, IL-6 and MCP-1. However, HDL had no effect on induction to the M2 phenotype. Similarly, methyl-beta-cyclodextrin (MβCD), a non-specific cholesterol acceptor was also able to suppress M1 induction suggesting cholesterol efflux is important in this process. Further we found that HDL decreased membrane caveolin-1 in M1 macrophages and redistributed it intracellularly. The requirement of caveolin-1 was revealed as bone marrow-derived macrophages from Cav-1-/- mice continued to differentiate into M1 despite the addition of HDL. Moreover, we demonstrated a decrease in STAT3 and ERK1/2 phosphorylation in M1 macrophages treated with HDL, suggesting cholesterol efflux inhibits the STAT3s and MAPKs during induction to the M1 phenotype. Finally, we found that HDL also inhibited M1 function; with reduced reactive oxygen species (ROS) production. We provide evidence that HDL reduces macrophage induction to the inflammatory M1 phenotype, but not M2, via cellular redistribution of caveolin-1 and inactivation of STAT3 and ERK1/2 signalling pathway.

MAPK p38/Ulk1 pathway inhibits autophagy and induces IL-1β expression in hepatic stellate cells

2022 ◽  
Author(s):  
Li Jin ◽  
Juan Li ◽  
ShuJuan Yang ◽  
Rou Zhang ◽  
Chunhua Hu ◽  
...  
Keyword(s):  
Immune Cells ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Hepatic Inflammation ◽  
The Past ◽  
Cytokine Induction ◽  
Cytokines And Chemokines ◽  
The Relationship ◽  
Autophagy Inhibition ◽  
Lps Treatment

Background: In the past, hepatic stellate cells (HSCs) were considered to be noninflammatory cells and contribute to liver fibrosis by producing extracellular matrix. Recently, it was found that HSCs can also secrete cytokines and chemokines and therefore participate in hepatic inflammation. Autophagy participates in many immune response processes in immune cells. It is unclear whether autophagy is involved in inflammatory cytokine induction in HSCs. Methods: MAPK p38, Ulk1 phosphorylation and the Ulk1-Atg13 complex were analyzed in HSC-T6 cells after LPS treatment. The relationship between autophagy inhibition and inflammation was investigated in primary rat HSCs. Results: We discovered that LPS inhibited autophagy through MAPK p38. The activation of MAPK p38 induced Ulk1 phosphorylation, which disrupted the Ulk1-Atg13 complex and therefore inhibited autophagy. Furthermore, in primary rat HSCs, we demonstrated that autophagy inhibition regulated IL-1β induction, which depended on the MAPK p38/Ulk1 pathway. Conclusions: Our results reveal a continuous signaling pathway, MAPK p38-Ulk1 phosphorylation-Ulk1/Atg13 disruption, which inhibits autophagy and induces IL-1β expression in HSCs.

Glycerol-3-phosphate acyltransferases 3 and 4 direct glycerolipid synthesis and affect functionality in activated macrophages

2019 ◽  
Vol 476 (1) ◽  
pp. 85-99 ◽  
Author(s):  
Ivana Y. Quiroga ◽  
Magali Pellon-Maison ◽  
Amanda L. Suchanek ◽  
Rosalind A. Coleman ◽  
Maria R. Gonzalez-Baro
Keyword(s):  
Lipid Accumulation ◽  
Macrophage Activation ◽  
Lipid A ◽  
Inflammatory Responses ◽  
Activated Macrophages ◽  
Phagocytic Capacity ◽  
Activity Increase ◽  
Cytokines And Chemokines ◽  
Lipid Mass ◽  
Glycerolipid Synthesis

AbstractMacrophage classical M1 activation via TLR4 triggers a variety of responses to achieve the elimination of foreign pathogens. During this process, there is also an increase in lipid droplets which contain large quantities of triacylglycerol (TAG) and phospholipid (PL). The functional consequences of this increment in lipid mass are poorly understood. Here, we studied the contribution of glycerolipid synthesis to lipid accumulation, focusing specifically on the first and rate-limiting enzyme of the pathway: glycerol-3-phosphate acyltransferase (GPAT). Using bone marrow-derived macrophages (BMDMs) treated with Kdo2-lipid A, we showed that glycerolipid synthesis is induced during macrophage activation. GPAT4 protein level and GPAT3/GPAT4 enzymatic activity increase during this process, and these two isoforms were required for the accumulation of cell TAG and PL. The phagocytic capacity of Gpat3−/− and Gpat4−/− BMDM was impaired. Additionally, inhibiting fatty acid β-oxidation reduced phagocytosis only partially, suggesting that lipid accumulation is not necessary for the energy requirements for phagocytosis. Finally, Gpat4−/− BMDM expressed and released more pro-inflammatory cytokines and chemokines after macrophage activation, suggesting a role for GPAT4 in suppressing inflammatory responses. Together, these results provide evidence that glycerolipid synthesis directed by GPAT4 is important for the attenuation of the inflammatory response in activated macrophages.

scholarly journals Genetic Code Expansion: A Powerful Tool for Understanding the Physiological Consequences of Oxidative Stress Protein Modifications

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Joseph J. Porter ◽  
Ryan A. Mehl
Keyword(s):  
Oxidative Stress ◽  
Genetic Code ◽  
Posttranslational Modifications ◽  
Stress Protein ◽  
Physiological Effects ◽  
The Past ◽  
Arduous Task ◽  
Therapeutic Development ◽  
Genetic Code Expansion ◽  
Antibody Validation

Posttranslational modifications resulting from oxidation of proteins (Ox-PTMs) are present intracellularly under conditions of oxidative stress as well as basal conditions. In the past, these modifications were thought to be generic protein damage, but it has become increasingly clear that Ox-PTMs can have specific physiological effects. It is an arduous task to distinguish between the two cases, as multiple Ox-PTMs occur simultaneously on the same protein, convoluting analysis. Genetic code expansion (GCE) has emerged as a powerful tool to overcome this challenge as it allows for the site-specific incorporation of an Ox-PTM into translated protein. The resulting homogeneously modified protein products can then be rigorously characterized for the effects of individual Ox-PTMs. We outline the strengths and weaknesses of GCE as they relate to the field of oxidative stress and Ox-PTMs. An overview of the Ox-PTMs that have been genetically encoded and applications of GCE to the study of Ox-PTMs, including antibody validation and therapeutic development, is described.

scholarly journals Annexin A2 is a soluble mediator of macrophage activation

2007 ◽  
Vol 82 (5) ◽  
pp. 1174-1184 ◽  
Author(s):  
Jennifer F. A. Swisher ◽  
Utsha Khatri ◽  
Gerald M. Feldman
Keyword(s):  
Macrophage Activation ◽  
Annexin A2 ◽  
Soluble Mediator

scholarly journals Adjuvant Activity of Emulsan, a Secreted Lipopolysaccharide from Acinetobacter calcoaceticus

2002 ◽  
Vol 9 (6) ◽  
pp. 1240-1247 ◽  
Author(s):  
Bruce Panilaitis ◽  
Atul Johri ◽  
Walter Blank ◽  
David Kaplan ◽  
Juliet Fuhrman
Keyword(s):  
Chemical Structure ◽  
Macrophage Activation ◽  
Acinetobacter Calcoaceticus ◽  
Dependent Manner ◽  
Adjuvant Activity ◽  
The Past ◽  
Antibody Titers ◽  
Human Use ◽  
Complex Polymer ◽  
Dose Dependent

ABSTRACT Several promising adjuvant candidates have been studied over the past 75 years; however, only alum is currently approved for human use. The complex acylated polysaccharide emulsan, secreted from Acinetobacter calcoaceticus, represents a new candidate. Unique features of this family of polymers are their amenability to structural tailoring and their emulsification behavior. We demonstrate that emulsan activates macrophages in a dose-dependent manner. This activation is dependent on the presence of the fatty acid side chains that decorate the polysaccharide backbone, and, furthermore, the level of activation can be affected by changes in the chemical characteristics of emulsan structural variants. One emulsan variant was examined in a classical hapten carrier immunization protocol and demonstrated significant adjuvant activity as determined by hapten-specific antibody titers. This immune response was characterized by a high immunoglobulin G2a titer, consistent with a Th1 response. The significant immunopotentiation demonstrated by this complex polymer establishes emulsan as an exciting new candidate adjuvant. Furthermore, by manipulating the chemical structure of this compound, we can explore the physical basis of pattern recognition receptors and macrophage activation.

scholarly journals Screening for Compounds That Modulate Epigenetic Regulation of the Transcriptome

2011 ◽  
Vol 16 (10) ◽  
pp. 1137-1152 ◽  
Author(s):  
Richard M. Eglen ◽  
Terry Reisine
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Posttranslational Modifications ◽  
High Throughput Screening ◽  
Dna Methyltransferases ◽  
Methylation Pattern ◽  
Gene Activity ◽  
Epigenetic Control ◽  
Dnmt Inhibitors ◽  
Inhibit Gene Expression

Epigenetic control of the transciptome is a complex and highly coordinated cellular process. One critical mechanism involves DNA methylation, mediated by distinct but related DNA methyltransferases (DNMTs). Although several DNMT inhibitors are available, most are nonselective; selective DNMT inhibitors, therefore, could be optimal as therapeutics, as well acting as chemical probes to elucidate the fundamental biology of individual DNMTs. DNA methylation is a stable chemical modification, yet posttranslational modification of histones is transitory, with reversible effects on gene expression. Histone posttranslational modifications influence access of transcription factors to DNA target sites to affect gene activity. Histones are regulated by several enzymes, including acetylases (HATs), deacetylases (HDACs), methyltransferases (HMTs), and demethylases (HDMTs). Generally, HATs activate, whereas HDACs suppress gene activity. Specifically, HMTs and HDMTs can either activate or inhibit gene expression, depending on the site and extent of the methylation pattern. There is growing interest in drugs that target enzymes involved in epigenetic control. Currently, a range of high-throughput screening (HTS) technologies are used to identify selective compounds against these enzymes. This review focuses on the rationale for drug development of these enzymes, as well the utility of HTS methods used in identifying and optimizing novel selective compounds that modulate epigenetic control of the human transcriptome.

Differentiation factors and cytokines in the atherosclerotic plaque micro-environment as a trigger for macrophage polarisation

2011 ◽  
Vol 106 (11) ◽  
pp. 763-771 ◽  
Author(s):  
Ine Wolfs ◽  
Marjo Donners ◽  
Menno de Winther
Keyword(s):  
Inflammatory Cell ◽  
Foam Cell ◽  
Cell Formation ◽  
Atherosclerotic Lesion ◽  
Foam Cell Formation ◽  
M1 Macrophages ◽  
Macrophage Polarisation ◽  
Atherosclerotic Lesions ◽  
Differentiation Factors

SummaryThe phenotype of macrophages in atherosclerotic lesions can vary dramatically, from a large lipid laden foam cell to a small inflammatory cell. Classically, the concept of macrophage heterogeneity discriminates between two extremes called either pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages. Polarisation of plaque macrophages is predominantly determined by the local micro-environment present in the atherosclerotic lesion and is rather more complex than typically described by the M1/M2 paradigm. In this review we will discuss the role of various polarising factors in regulating the phenotypical state of plaque macrophages. We will focus on two main levels of phenotype regulation, one determined by differentiation factors produced in the lesion and the other determined by T-cell-derived polarising cytokines. With foam cell formation being a key characteristic of macrophages during atherosclerosis initiation and progression, these polarisation factors will also be linked to lipid handling of macrophages.

Effect of Electrospun Fiber Diameter and Alignment on Macrophage Activation and Secretion of Proinflammatory Cytokines and Chemokines

2011 ◽  
Vol 12 (5) ◽  
pp. 1900-1911 ◽  
Author(s):  
Enrica Saino ◽  
Maria Letizia Focarete ◽  
Chiara Gualandi ◽  
Enzo Emanuele ◽  
Antonia I. Cornaglia ◽  
...  
Keyword(s):  
Proinflammatory Cytokines ◽  
Macrophage Activation ◽  
Fiber Diameter ◽  
Electrospun Fiber ◽  
Cytokines And Chemokines

scholarly journals eIF-Three to Tango: Emerging Functions of Translation Initiation Factor eIF3 in Protein Synthesis and Disease

2019 ◽  
Author(s):  
Dieter A. Wolf ◽  
Yingying Lin ◽  
Haoran Duan ◽  
Yabin Cheng
Keyword(s):  
Protein Synthesis ◽  
Posttranslational Modifications ◽  
Protein Production ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Protein Homeostasis ◽  
Subcellular Targeting ◽  
The Past ◽  
Different Tissues

Studies over the past three years have substantially expanded the involvements of eIF3 in mRNA translation. It now appears that this multi-subunit complex is involved in every possible form of mRNA translation, controlling every step of protein synthesis from initiation to elongation, termination and quality control in positive as well as negative fashion. Through the study of eIF3, we are beginning to appreciate protein synthesis as a highly integrated process coordinating protein production with protein folding, subcellular targeting, and degradation. At the same time, eIF3 subunits appear to have specific functions that probably vary between different tissues and individual cells. Considering the broad functions of eIF3 in protein homeostasis, it comes as little surprise that eIF3 is increasingly implicated in major human diseases and first attempts at therapeutically targeting eIF3 have been undertaken. Much remains to be learned, however, about subunit- and tissue-specific functions of eIF3 in protein synthesis and disease and their regulation by environmental conditions and posttranslational modifications.

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