scholarly journals Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells

Hepatology ◽  
2011 ◽  
Vol 54 (1) ◽  
pp. 133-144 ◽  
Author(s):  
Timea Csak ◽  
Michal Ganz ◽  
Justin Pespisa ◽  
Karen Kodys ◽  
Angela Dolganiuc ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Immune Cells ◽  
Danger Signals ◽  
Mouse Hepatocytes

scholarly journals Metabolic Factors Affecting Tumor Immunogenicity: What Is Happening at the Cellular Level?

2021 ◽  
Vol 22 (4) ◽  
pp. 2142
Author(s):  
Rola El Sayed ◽  
Yolla Haibe ◽  
Ghid Amhaz ◽  
Youssef Bouferraa ◽  
Ali Shamseddine
Keyword(s):  
Fatty Acid ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Immune Modulation ◽  
Checkpoint Inhibitors ◽  
Therapeutic Option ◽  
Effector Memory ◽  
Acid Oxidation ◽  
Checkpoint Inhibition ◽  
Inflammatory Phenotypes

Immunotherapy has changed the treatment paradigm in multiple solid and hematologic malignancies. However, response remains limited in a significant number of cases, with tumors developing innate or acquired resistance to checkpoint inhibition. Certain “hot” or “immune-sensitive” tumors become “cold” or “immune-resistant”, with resultant tumor growth and disease progression. Multiple factors are at play both at the cellular and host levels. The tumor microenvironment (TME) contributes the most to immune-resistance, with nutrient deficiency, hypoxia, acidity and different secreted inflammatory markers, all contributing to modulation of immune-metabolism and reprogramming of immune cells towards pro- or anti-inflammatory phenotypes. Both the tumor and surrounding immune cells require high amounts of glucose, amino acids and fatty acids to fulfill their energy demands. Thus, both compete over one pool of nutrients that falls short on needs, obliging cells to resort to alternative adaptive metabolic mechanisms that take part in shaping their inflammatory phenotypes. Aerobic or anaerobic glycolysis, oxidative phosphorylation, tryptophan catabolism, glutaminolysis, fatty acid synthesis or fatty acid oxidation, etc. are all mechanisms that contribute to immune modulation. Different pathways are triggered leading to genetic and epigenetic modulation with consequent reprogramming of immune cells such as T-cells (effector, memory or regulatory), tumor-associated macrophages (TAMs) (M1 or M2), natural killers (NK) cells (active or senescent), and dendritic cells (DC) (effector or tolerogenic), etc. Even host factors such as inflammatory conditions, obesity, caloric deficit, gender, infections, microbiota and smoking status, may be as well contributory to immune modulation, anti-tumor immunity and response to immune checkpoint inhibition. Given the complex and delicate metabolic networks within the tumor microenvironment controlling immune response, targeting key metabolic modulators may represent a valid therapeutic option to be combined with checkpoint inhibitors in an attempt to regain immune function.

scholarly journals Lipid and glucose metabolism in hepatocyte cell lines and primary mouse hepatocytes: a comprehensive resource for in vitro studies of hepatic metabolism

2019 ◽  
Vol 316 (4) ◽  
pp. E578-E589 ◽  
Author(s):  
Shilpa R. Nagarajan ◽  
Moumita Paul-Heng ◽  
James R. Krycer ◽  
Daniel J. Fazakerley ◽  
Alexandra F. Sharland ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Glucose Metabolism ◽  
Cell Lines ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Primary Hepatocytes ◽  
Primary Mouse Hepatocytes ◽  
Primary Mouse ◽  
Mouse Hepatocytes

The liver is a critical tissue for maintaining glucose, fatty acid, and cholesterol homeostasis. Primary hepatocytes represent the gold standard for studying the mechanisms controlling hepatic glucose, lipid, and cholesterol metabolism in vitro. However, access to primary hepatocytes can be limiting, and therefore, other immortalized hepatocyte models are commonly used. Here, we describe substrate metabolism of cultured AML12, IHH, and PH5CH8 cells, hepatocellular carcinoma-derived HepG2s, and primary mouse hepatocytes (PMH) to identify which of these cell lines most accurately phenocopy PMH basal and insulin-stimulated metabolism. Insulin-stimulated glucose metabolism in PH5CH8 cells, and to a lesser extent AML12 cells, responded most similarly to PMH. Notably, glucose incorporation in HepG2 cells were 14-fold greater than PMH. The differences in glucose metabolic activity were not explained by differential protein expression of key regulators of these pathways, for example glycogen synthase and glycogen content. In contrast, fatty acid metabolism in IHH cells was the closest to PMHs, yet insulin-responsive fatty acid metabolism in AML12 and HepG2 cells was most similar to PMH. Finally, incorporation of acetate into intracellular-free cholesterol was comparable for all cells to PMH; however, insulin-stimulated glucose conversion into lipids and the incorporation of acetate into intracellular cholesterol esters were strikingly different between PMHs and all tested cell lines. In general, AML12 cells most closely phenocopied PMH in vitro energy metabolism. However, the cell line most representative of PMHs differed depending on the mode of metabolism being investigated, and so careful consideration is needed in model selection.

1314 Abomasal infusions of linoleic and linolenic acid in lactating dairy cows differentially alter the fatty acid composition of plasma lipid fractions and immune cells

2016 ◽  
Vol 94 (suppl_5) ◽  
pp. 633-633
Author(s):  
S. E. Schmidt ◽  
V. E. Ryman ◽  
C. L. Preseault ◽  
L. M. Sordillo ◽  
A. L. Lock
Keyword(s):  
Fatty Acid Composition ◽  
Fatty Acid ◽  
Dairy Cows ◽  
Linolenic Acid ◽  
Acid Composition ◽  
Immune Cells ◽  
Plasma Lipid ◽  
Lactating Dairy Cows ◽  
Lipid Fractions

scholarly journals Transcriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1411 ◽  
Author(s):  
Irina Larionova ◽  
Elena Kazakova ◽  
Marina Patysheva ◽  
Julia Kzhyshkowska
Keyword(s):  
Fatty Acid ◽  
Immune Cells ◽  
Tumor Response ◽  
Macrophage Polarization ◽  
Innate Immune ◽  
Acid Oxidation ◽  
Innate Immune Cells ◽  
Primary Tumor Growth ◽  
Tumor Microenvironments ◽  
Functional Polarization

Macrophages are key innate immune cells in the tumor microenvironment (TME) that regulate primary tumor growth, vascularization, metastatic spread and tumor response to various types of therapies. The present review highlights the mechanisms of macrophage programming in tumor microenvironments that act on the transcriptional, epigenetic and metabolic levels. We summarize the latest knowledge on the types of transcriptional factors and epigenetic enzymes that control the direction of macrophage functional polarization and their pro- and anti-tumor activities. We also focus on the major types of metabolic programs of macrophages (glycolysis and fatty acid oxidation), and their interaction with cancer cells and complex TME. We have discussed how the regulation of macrophage polarization on the transcriptional, epigenetic and metabolic levels can be used for the efficient therapeutic manipulation of macrophage functions in cancer.

scholarly journals Dietary supplementation with trans-11- and trans-12-18 : 1 increases cis-9, trans-11-conjugated linoleic acid in human immune cells, but without effects on biomarkers of immune function and inflammation

2007 ◽  
Vol 97 (6) ◽  
pp. 1196-1205 ◽  
Author(s):  
Katrin Kuhnt ◽  
Jana Kraft ◽  
Heinz Vogelsang ◽  
Klaus Eder ◽  
Jürgen Kratzsch ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Immune Function ◽  
Immune Cells ◽  
Test Group ◽  
Dietary Supplementation ◽  
Adaptation Period ◽  
Fatty Acid Intake ◽  
Acid Intake ◽  
Increased Risk ◽  
Cellular Lipids

Trans-fatty acid intake is associated with an increased risk of CHD and diabetes. The effects of single trans-fatty acid isomers are largely unexplored. The present study examined the effects of a 6-week supplementation with two trans-18 : 1 isomers (trans-11 and trans-12) in human subjects on immune cells, several inflammatory and immunological biomarkers (for example, IL, TNFα, C-reactive protein, adiponectin, intercellular adhesion molecule-1, prostacyclin, phagocytic process). Following a 2-week adaptation period without supplements, the test group (n 12) received vaccenic acid (trans-11-18:1) and trans-12-18 : 1 in equal amounts (6·0 g/d) for 6 weeks. The control group (n 12) consumed an oil without trans-fatty acids and conjugated linoleic acids (CLA). Samples were collected at the end of both periods. Trans-11- and trans-12-18 : 1 were significantly increased in cellular lipids. The endogenous synthesis of cis-9, trans-11-CLA from trans-11-18 : 1 was demonstrated via increased CLA in cellular lipids of the test group. Generally, trans-isomer supplementation did not affect either inflammatory biomarkers (for example, IL-6, IL-8, TNFα) or immune function (for example, phagocytosis) during the present study. The dietary supplementation of trans-11- and trans-12-18 : 1 (6 g/d) and their accumulation in leucocytes had no effects on biomarkers of inflammation and immune function. However, because of the limited data on the safety of trans-fatty acid intake and effects of individual trans isomers on human health (for example, trans-9-18 : 1, trans-10-18 : 1) at present, it is prudent to reduce trans-fat intake in general.

scholarly journals Spatiotemporal Cellular Networks Maintain Immune Homeostasis in the Lung

2020 ◽  
Author(s):  
Jessica Borger
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Respiratory Epithelium ◽  
Physical Barrier ◽  
Pulmonary Tissue ◽  
Danger Signals ◽  
Cell Network ◽  
Defence Proteins ◽  
Molecular Signals ◽  
Lung Immunity

A dynamic and intricately connected tissue-resident immune cell network continuously monitors the lungs, which are incessantly subjected to external environmental insults. The lungs are protected by the respiratory epithelium, which not only serves as a physical barrier through mucociliary mechanisms, but also a reactive one that can release cytokines, chemokines, and other defence proteins in response to danger signals. In the maintenance of pulmonary homeostasis in health, the lung-resident immune cell network instructs tolerance to innocuous particulates and can rapidly and efficiently drive immunity and memory to pathogenic antigens. This review examines the spatiotemporal dynamics that underlie the exquisite network of highly specialised immune cells and their mediators in the support of pulmonary tissue homeostasis and effective lung immunity in health. In particular, this review examines the specialised immune cells that reside in distinct populations within the diverse compartments of the lung, and the molecular signals that retain and recruit lung-resident immune cells, to further our understanding of how these can be targeted therapeutically to return inflamed or diseased lungs to homeostasis.

scholarly journals Immunohistochemical Study of ASC Expression and Distribution in the Hippocampus of an Aged Murine Model of Alzheimer’s Disease

2021 ◽  
Vol 22 (16) ◽  
pp. 8697
Author(s):  
Diana Reimers ◽  
Manuela Vallejo-Muñoz ◽  
María José Casarejos ◽  
Adriano Jimenez-Escrig ◽  
Rafael Gonzalo-Gobernado ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Cells ◽  
Immunohistochemical Study ◽  
Transgenic Mouse Model ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Danger Signals ◽  
Model Of Alzheimer’S Disease ◽  
Pro Inflammatory Cytokines

Neuroinflammation is involved in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD), and is notably dependent on age. One important inflammatory pathway exerted by innate immune cells of the nervous system in response to danger signals is mediated by inflammasomes (IF) and leads to the generation of potent pro-inflammatory cytokines. The protein “apoptosis-associated speck-like protein containing a caspase recruitment domain” (ASC) modulates IF activation but has also other functions which are crucial in AD. We intended to characterize immunohistochemically ASC and pattern recognition receptors (PRR) of IF in the hippocampus (HP) of the transgenic mouse model Tg2576 (APP), in which amyloid-beta (Aβ) pathology is directly dependent on age. We show in old-aged APP a significant amount of ASC in microglia and astrocytes associated withAβ plaques, in the absence of PRR described by others in glial cells. In addition, APP developed foci with clusters of extracellular ASC granules not spatiallyrelated to Aβ plaques, which density correlated with the advanced age of mice and AD development. Clusters were associated withspecific astrocytes characterized by their enlarged ring-shaped process terminals, ASC content, and frequent perivascular location. Their possible implication in ASC clearance and propagation of inflammation is discussed.

scholarly journals Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2579
Author(s):  
Diana Oelschlaegel ◽  
Tommy Weiss Sadan ◽  
Seth Salpeter ◽  
Sebastian Krug ◽  
Galia Blum ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Immune Cells ◽  
Fatty Acid Synthase ◽  
Acid Metabolism ◽  
Metabolic Reprogramming ◽  
Marker Genes ◽  
Tumor Associated Macrophages ◽  
Cathepsin Activity ◽  
The Impact

Stroma-infiltrating immune cells, such as tumor-associated macrophages (TAM), play an important role in regulating tumor progression and chemoresistance. These effects are mostly conveyed by secreted mediators, among them several cathepsin proteases. In addition, increasing evidence suggests that stroma-infiltrating immune cells are able to induce profound metabolic changes within the tumor microenvironment. In this study, we aimed to characterize the impact of cathepsins in maintaining the TAM phenotype in more detail. For this purpose, we investigated the molecular effects of pharmacological cathepsin inhibition on the viability and polarization of human primary macrophages as well as its metabolic consequences. Pharmacological inhibition of cathepsins B, L, and S using a novel inhibitor, GB111-NH2, led to changes in cellular recycling processes characterized by an increased expression of autophagy- and lysosome-associated marker genes and reduced adenosine triphosphate (ATP) content. Decreased cathepsin activity in primary macrophages further led to distinct changes in fatty acid metabolites associated with increased expression of key modulators of fatty acid metabolism, such as fatty acid synthase (FASN) and acid ceramidase (ASAH1). The altered fatty acid profile was associated with an increased synthesis of the pro-inflammatory prostaglandin PGE2, which correlated with the upregulation of numerous NFkB-dependent pro-inflammatory mediators, including interleukin-1 (IL-1), interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), and tumor necrosis factor-alpha (TNFα). Our data indicate a novel link between cathepsin activity and metabolic reprogramming in macrophages, demonstrated by a profound impact on autophagy and fatty acid metabolism, which facilitates a pro-inflammatory micromilieu generally associated with enhanced tumor elimination. These results provide a strong rationale for therapeutic cathepsin inhibition to overcome the tumor-promoting effects of the immune-evasive tumor micromilieu.

P139 EFFECT OF LYSOSOMAL SHORT CHAIN FATTY ACID DELIVERY ON IMMUNE RESPONSE

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S12-S12
Author(s):  
Simon Strass ◽  
Constanze Heinzel ◽  
Natascha Cloos ◽  
Manuel Keppler ◽  
Jan Guse ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Immune Cells ◽  
Immune Modulation ◽  
Cytokine Production ◽  
Short Chain ◽  
Control Group ◽  
U937 Cells ◽  
Effective Response ◽  
Error Bars ◽  
Stimulation Of

Abstract Short chain fatty acids (SCFAs) are known as metabolites produced from gut microbiome fermenting dietary fibers and resistant starch. They are regulators of the interplay between the microbiome and its host and may have a role in the pathogenesis of inflammatory bowel disease (IBD). Free SCFAs influence intestinal epithelial and immune cells (e.g. macrophages and primary monocytes) through activation of free fatty acid receptors FFAR2 and FFAR3, inhibition of histone deacetylases (HDAC) and as a source of energy. SCFAs are known to impact cytokine production and differentiation of immune cells (e.g. Tumor necrosis factor alpha (TNFa), Interleukin (IL)-10, IL-6, IL-18, IL-1ß). We investigated the role of SCFAs in dextran sulfate sodium-induced colitis and their effect on the cytokine production by primary human immune cells. Treatment with SCFAs (acetate, propionate or butyrate) stimulated release of IL-1ß and IL-18 by buffy coat leukocytes or U937 cells without causing increased expression of corresponding genes. This raises the possibility of activation via the NLRP3 (NOD-, LRR- and pyrin domain- containing protein 3) inflammasome. NLRP3 is a multimeric inflammasome complex. Once activated, NLRP3 inflammasome releases caspase 1 leading to formation of mature IL-1ß and IL-18. Recent studies have shown that IL-1ß promotes phagocytosis and clearance of bacteria and aids the gut in eliciting an effective response in early stages of IBD. We asked whether this effect is mediated via surface or lysosomal (phagosomal) receptors? To answer this question, we prepared a series (SYD010) of novel compounds which are able to accumulate in the phagolysosome of immune cells through their macrolide backbone and deliver SCFAs, bound as esters to the lumen of the activated lysosome. In vitro, together with LPS stimulation, the substances modulated secretion of TNFa, IL-1ß, IL-10 and IL-6 at concentrations about 100x lower than free SCFAs (Figure 1). When tested in a DSS colitis mouse model, the SYD010 series caused a decrease in diarrhea scoring compared to the vehicle-treated control group at a concentration of 0.1 mg/kg (Figure 2) which corresponds to a total dose of ca. 100 nmol/kg (the compounds are systemically distributed). This is lower than the known luminal concentrations of SCFAs which is in the range of 40 mM. Our underlying hypothesis is that lysosomal reception of SCFAs leads to beneficial immune modulation in colitis in so far as stimulation of IL-1ß release promotes bacterial clearance. Furthermore, that concentrative uptake to the phagolysosome leads to enhanced stimulation of these receptors leading to responses at lower ambient concentrations or doses. We are assessing this substance class as potential IBD therapeutics. Figure 1. Effect of sodium butyrate or CSY4286 (lysosomal butyrate donor) on cytokine production by U937 cells. Supernatants were harvested after 24 h (IL-6) and 48 h (IL-1ß, IL-6) incubation with the test substances and cytokines determined by ELISA. The dotted line represents levels with LPS stimulation alone. SEM was applied for error bars. Figure 2. Results from DSS-induced (2.5% in drinking water) IBD study in BALB/c mice (8 mice per group). Scoring of body weight and diarrhea score over 8 days (a and b show data from final day of study). SEM was applied for error bars.

scholarly journals NLRP3 Inflammasome and IL-33: Novel Players in Sterile Liver Inflammation

2018 ◽  
Vol 19 (9) ◽  
pp. 2732 ◽  
Author(s):  
Katrin Neumann ◽  
Birgit Schiller ◽  
Gisa Tiegs
Keyword(s):  
Immune System ◽  
Liver Disease ◽  
Immune Cells ◽  
Nlrp3 Inflammasome ◽  
Tissue Injury ◽  
Therapeutic Strategies ◽  
Liver Inflammation ◽  
Danger Signal ◽  
Danger Signals ◽  
Anti Inflammatory

In sterile liver inflammation, danger signals are released in response to tissue injury to alert the immune system; e.g., by activation of the NLRP3 inflammasome. Recently, IL-33 has been identified as a novel type of danger signal or “alarmin”, which is released from damaged and necrotic cells. IL-33 is a pleiotropic cytokine that targets a broad range of immune cells and exhibits pro- and anti-inflammatory properties dependent on the disease. This review summarizes the immunomodulatory roles of the NLRP3 inflammasome and IL-33 in sterile liver inflammation and highlights potential therapeutic strategies targeting these pathways in liver disease.

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