Browse
Submit Data
Databases
API
Help

Dataset Information

33 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Macrophages rely on extracellular serine to suppress aberrant cytokine production.

ABSTRACT: A growing body of evidence indicates that cellular metabolism is involved in immune cell functions, including cytokine production. Serine is a nutritionally non-essential amino acid that can be generated by de novo synthesis and conversion from glycine. Serine contributes to various cellular responses, but the role in inflammatory responses remains poorly understood. Here, we show that macrophages rely on extracellular serine to suppress aberrant cytokine production. Depleting serine from the culture media reduced the cellular serine content in macrophages markedly, suggesting that macrophages depend largely on extracellular serine rather than cellular synthesis. Under serine deprivation, macrophages stimulated with lipopolysaccharide showed aberrant cytokine expression patterns, including a marked reduction of anti-inflammatory interleukin-10 expression and sustained expression of interleukine-6. Transcriptomic and metabolomics analyses revealed that serine deprivation causes mitochondrial dysfunction: reduction in the pyruvate content, the NADH/NAD⁺ ratio, the oxygen consumption rate, and the mitochondrial production of reactive oxygen species (ROS). We also found the role of mitochondrial ROS in appropriate cytokine production. Thus, our results indicate that cytokine production in macrophages is tightly regulated by the nutritional microenvironment.

SUBMITTER: Kurita K

PROVIDER: S-EPMC8160356 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Maxed Out on Glycolysis: Alveolar Macrophages Rely on Oxidative Phosphorylation for Cytokine Production.

Project description: Not available

| S-EPMC6993550 | biostudies-literature

Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis.

Project description:Secretion of the cytokine interleukin-1? (IL-1?) by macrophages, a major driver of pathogenesis in atherosclerosis, requires two steps: Priming signals promote transcription of immature IL-1?, and then endogenous "danger" signals activate innate immune signaling complexes called inflammasomes to process IL-1? for secretion. Although cholesterol crystals are known to act as danger signals in atherosclerosis, what primes IL-1? transcription remains elusive. Using a murine model of atherosclerosis, we found that cholesterol crystals acted both as priming and danger signals for IL-1? production. Cholesterol crystals triggered neutrophils to release neutrophil extracellular traps (NETs). NETs primed macrophages for cytokine release, activating T helper 17 (TH17) cells that amplify immune cell recruitment in atherosclerotic plaques. Therefore, danger signals may drive sterile inflammation, such as that seen in atherosclerosis, through their interactions with neutrophils.

| S-EPMC4854322 | biostudies-literature

Extracellular Vesicles from Apoptotic Cells Promote TGFβ Production in Macrophages and Suppress Experimental Colitis.

Project description:The clearance of apoptotic cells is an essential process to maintain homeostasis of immune system, which is regulated by immunoregulatory cytokines such as TGFβ. We show here that Extracellular Vesicles (EVs) were highly released from apoptotic cells, and contributed to macrophage production of TGFβ in vitro and in vivo. We further elucidated mechanistically that phosphatidylserine in EVs was a key triggering-factor, and transcription factor FOXO3 was a critical mediator for apoptotic EV-induced TGFβ in macrophages. Importantly, we found that macrophages pre-exposed to EVs exhibited an anti-inflammatory phenotype. More strikingly, administration of EVs in vivo promotes Tregs differentiation and suppresses Th1 cell response, and ameliorates experimental colitis. Thus, apoptotic-EV-based treatment might be a promising therapeutic approach for human autoimmune disease.

| S-EPMC6458171 | biostudies-literature

Cell sorting enriches Escherichia coli mutants that rely on peptidoglycan endopeptidases to suppress highly aberrant morphologies.

Project description:Bacterial morphology imparts physiological advantages to cells in different environments and, judging by the fidelity with which shape is passed to daughter cells, is a tightly regulated characteristic. Surprisingly, only in the past 10 to 15 years has significant headway been made in identifying the mechanisms by which cells create and maintain particular shapes. One reason for this is that the relevant discoveries have relied heavily on the arduous, somewhat subjective process of manual microscopy. Here, we show that flow cytometry, coupled with the sorting capability of fluorescence-activated cell sorting (FACS), can detect, quantify, and enrich bacteria with morphological alterations. The light scattering properties of several highly aberrant morphological mutants of Escherichia coli were characterized by flow cytometry. Cells from a region that overlapped the distribution of normal rod-shaped cells were collected by FACS and reincubated. After 4 to 15 iterations of this enrichment process, suppressor mutants were isolated that returned almost all the population to a near-normal shape. Suppressors were successfully isolated from strains lacking three or four penicillin binding proteins (PBPs) but not from a mutant lacking a total of seven PBPs. The peptidoglycan endopeptidase, AmpH, was identified as being important for the suppression process, as was a related endopeptidase, MepA. The results validate the use of cell sorting as a means for studying bacterial morphology and identify at least one new class of enzymes required for the suppression of cell shape defects.

| S-EPMC3562112 | biostudies-literature

Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis.

Project description:Macrophage-specific expression of Arginase-1 is commonly believed to promote inflammation, fibrosis, and wound healing by enhancing L-proline, polyamine, and Th2 cytokine production. Here, however, we show that macrophage-specific Arg1 functions as an inhibitor of inflammation and fibrosis following infection with the Th2-inducing pathogen Schistosoma mansoni. Although susceptibility to infection was not affected by the conditional deletion of Arg1 in macrophages, Arg1(-/flox);LysMcre mice died at an accelerated rate. The mortality was not due to acute Th1/NOS2-mediated hepatotoxicity or endotoxemia. Instead, granulomatous inflammation, liver fibrosis, and portal hypertension increased in infected Arg1(-/flox);LysMcre mice. Similar findings were obtained with Arg1(flox/flox);Tie2cre mice, which delete Arg1 in all macrophage populations. Production of Th2 cytokines increased in the infected Arg1(-/flox);LysMcre mice, and unlike alternatively activated wild-type macrophages, Arg1(-/flox);LysMcre macrophages failed to inhibit T cell proliferation in vitro, providing an underlying mechanism for the exacerbated Th2 pathology. The suppressive activity of Arg1-expressing macrophages was independent of IL-10 and TGF-beta1. However, when exogenous L-arginine was provided, T cell proliferation was restored, suggesting that Arg1-expressing macrophages deplete arginine, which is required to sustain CD4(+) T cell responses. These data identify Arg1 as the essential suppressive mediator of alternatively activated macrophages (AAM) and demonstrate that Arg1-expressing macrophages function as suppressors rather than inducers of Th2-dependent inflammation and fibrosis.

| S-EPMC2660425 | biostudies-literature

Neutrophil Extracellular Traps Promote Aberrant Macrophages Activation in Behcet's Disease.

Project description:Neutrophil extracellular traps (NETs) are upregulated and promote thrombosis in Behçet's disease (BD). However, whether NETs promote autoinflammation in BD remains unclear. This study aimed to investigate the potential role of NETs in promoting macrophage activation in BD. Firstly, we quantified NETs by measuring double-stranded DNA (dsDNA) using PicoGreen and calculating the proportion of NETosis. Then macrophages were stimulated with BD- or healthy controls (HC)-derived NETs, and IL-8 and TNF-α production and IFN-γ+ CD4+ T cells differentiation were measured using ELISA and flow cytometry, respectively. The protein components in NETs were analyzed by western blot. Macrophages were stimulated with Histone H4 neutralized NETs, and IL-8 and TNF-α production were measured using ELISA. The level of 8-hydroxydeoxyguanosine (8-OHdG) DNA in NETs was measured using ELISA. The levels of reactive oxygen species (ROS) in serum and neutrophils were measured using ROS probes by a microplate reader and flow cytometry. We found that circulating NETs and neutrophil-derived NETs were significantly higher in BD than HC. BD NETs stimulated macrophages produced higher levels of IL-8 and TNF-α, and promoted IFN-γ+ CD4+ T cells differentiation. BD NETs were enriched in Histone H4, and neutralizing Histone H4 abrogated the BD NETs-mediated IL-8 production by macrophages, but not TNF-α. Also, BD neutrophils produced more 8-OHdG DNA than HC neutrophils, and the percentage of 8-OHdG DNA in dsDNA from BD neutrophils was also higher than that of HC neutrophils. The ROS levels in serum and neutrophils were both higher in BD than HC. Our findings suggested that excessive BD NETs promoted macrophages activation and facilitated IFN-γ+ CD4+ T cells differentiation. Higher levels of Histone H4 and oxidized DNA in BD NETs might mediate macrophages hyperactivation.

| S-EPMC7901995 | biostudies-literature

Serine Supports IL-1? Production in Macrophages Through mTOR Signaling.

Project description:Intracellular metabolic programs tightly regulate the functions of macrophages, and previous studies have shown that serine mainly shapes the macrophage function via one-carbon metabolism. However, it is unknown whether serine modulates the macrophage function independent of one-carbon metabolism. Here, we find that serine deprivation lowers interleukin (IL)-1? production and inflammasome activation, as well as reprograms the transcriptomic and metabolic profile in M1 macrophages. Intriguingly, supplementation of formate, glycine, dNTPs, and glucose cannot rescue the production of IL-1? from serine-deprived macrophages. Mechanistically, serine deprivation inhibits macrophage IL-1? production through inhibition of mechanistic target of rapamycin (mTOR) signaling. Of note, the macrophages from mice feeding serine-free diet have lower IL-1? production, and these mice also show less inflammation after LPS challenge. Collectively, our data highlight a new regulatory mechanism for serine to modulate the macrophage function.

| S-EPMC7481448 | biostudies-literature

Ultrashort cationic lipopeptides and lipopeptoids selectively induce cytokine production in macrophages.

Project description:A series of ultrashort lipopeptides and lipopeptoids were tested for their ability to induce cytokine production in macrophages. Fourteen compounds were found to strongly induce production of chemokines Gro? and IL-8, with a structural bias that was absent from previous antibacterial activity investigations. Compounds based on LysGlyLys and NLysGlyNLys sequences did not induce cytokine production, whereas those based on LysLysLys and NLysNLysNLys were active only when linked to a lipid tail at least sixteen carbons long. Three lipopeptides induced high levels of IL-8 production, above that of equivalent concentrations of cathelicidin LL-37, while no compound induced production of the pro-inflammatory cytokine TNF-? at or below 100 µM. Two compounds, peptoids C16OH-NLysNLysNLys and C16OH-NHarNHarNHar, were selective for IL-8 production and did not induce TNF-? or IL-1?. These compounds may prove beneficial for in vivo treatment of infectious disease, with improved bioavailability over LL-37 due to their protease-resistant scaffold.

| S-EPMC3563528 | biostudies-literature

Modulating Cytokine Production via Select Packaging and Secretion From Extracellular Vesicles.

Project description:Cytokines are soluble factors that play vital roles in systemic function due to their ability to initiate and mediate cell-to-cell communication. Another important mechanism of intercellular communication that has gained significant attention in the past 10 years is the release of extracellular vesicles (EVs). EVs are released by all cells during normal physiology, in states of resting and activation, as well as during disease. Accumulating evidence indicates that cytokines may be packaged into EVs, and the packaging of cytokines into EVs, along with their ultimate secretion, may also be regulated by cytokines. Importantly, the repertoire of biomolecules packaged into EVs is shaped by the biological state of the cell (resting vs. activated and healthy vs. disease) and the EV biogenesis pathway involved, thus providing mechanisms by which EV packaging and secretion may be modulated. Given the critical role of cytokines in driving acute and chronic inflammatory and autoimmune diseases, as well as their role in establishing the tumor immune microenvironment, in this review, we will focus on these disease settings and summarize recent progress and mechanisms by which cytokines may be packaged within and modulated by EVs, as a therapeutic option for regulating innate and adaptive immunity.

| S-EPMC7272603 | biostudies-literature

FoxO1 links insulin resistance to proinflammatory cytokine IL-1beta production in macrophages.

Project description:ObjectiveMacrophages play an important role in the pathogenesis of insulin resistance via the production of proinflammatory cytokines. Our goal is to decipher the molecular linkage between proinflammatory cytokine production and insulin resistance in macrophages.Research design and methodsWe determined cytokine profiles in cultured macrophages and identified interleukin (IL)-1? gene as a potential target of FoxO1, a key transcription factor that mediates insulin action on gene expression. We studied the mechanism by which FoxO1 mediates insulin-dependent regulation of IL-1? expression in cultured macrophages and correlated FoxO1 activity in peritoneal macrophages with IL-1? production profiles in mice with low-grade inflammation or insulin resistance.ResultsFoxO1 selectively promoted IL-1? production in cultured macrophages. This effect correlated with the ability of FoxO1 to bind and enhance IL-1? promoter activity. Mutations of the FoxO1 binding site within the IL-1? promoter abolished FoxO1 induction of IL-1? expression. Macrophages from insulin-resistant obese db/db mice or lipopolysaccharide-inflicted mice were associated with increased FoxO1 production, correlating with elevated levels of IL-1? mRNA in macrophages and IL-1 protein in plasma. In nonstimulated macrophages, FoxO1 remained inert with benign effects on IL-1? expression. In response to inflammatory stimuli, FoxO1 activity was augmented because of an impaired ability of insulin to phosphorylate FoxO1 and promote its nuclear exclusion. This effect along with nuclear factor-?B acted to stimulate IL-1? production in activated macrophages.ConclusionsFoxO1 signaling through nuclear factor-?B plays an important role in coupling proinflammatory cytokine production to insulin resistance in obesity and diabetes.

| S-EPMC2768186 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data