Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Mitohormesis reprograms macrophage metabolism to enforce tolerance [vWAT_mac_RNAseq]

ABSTRACT: Macrophages generate mitochondrial reactive oxygen and electrophilic species (mtROS, mtRES) as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here, we demonstrate that both pharmacologically- and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state where stimulus-induced proinflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, hydroxyestrogen-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and proinflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mtROS and mtRES are TLR-dependent signaling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signaling and pharmacologically triggering mitohormesis represents a novel anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of proinflammatory gene transcription by mitochondria.

ORGANISM(S): Mus musculus

PROVIDER: GSE169728 | GEO | 2021/04/04

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Mitohormesis reprograms macrophage metabolism to enforce tolerance [BMDM_OHestrogen_RNAseq]

Project description:Macrophages generate mitochondrial reactive oxygen and electrophilic species (mtROS, mtRES) as antimicrobials during Toll-like receptor (TLR)-dependent inflammatory responses. Whether mitochondrial stress caused by these molecules impacts macrophage function is unknown. Here, we demonstrate that both pharmacologically- and lipopolysaccharide (LPS)-driven mitochondrial stress in macrophages triggers a stress response called mitohormesis. LPS-driven mitohormetic stress adaptations occur as macrophages transition from an LPS-responsive to LPS-tolerant state where stimulus-induced proinflammatory gene transcription is impaired, suggesting tolerance is a product of mitohormesis. Indeed, like LPS, hydroxyestrogen-triggered mitohormesis suppresses mitochondrial oxidative metabolism and acetyl-CoA production needed for histone acetylation and proinflammatory gene transcription, and is sufficient to enforce an LPS-tolerant state. Thus, mtROS and mtRES are TLR-dependent signaling molecules that trigger mitohormesis as a negative feedback mechanism to restrain inflammation via tolerance. Moreover, bypassing TLR signaling and pharmacologically triggering mitohormesis represents a novel anti-inflammatory strategy that co-opts this stress response to impair epigenetic support of proinflammatory gene transcription by mitochondria.

2021-04-04 | GSE169727 | GEO

Mitohormesis reprograms macrophage metabolism to enforce tolerance [BMDM_ChIPseq]

2021-04-04 | GSE169729 | GEO

Mitohormesis reprograms macrophage metabolism to enforce tolerance [BMDM_tolerance_RNAseq]

2021-04-04 | GSE169730 | GEO

Transcription profiling of mouse naive and tolerant macrophages stimulated with LPS

Project description:The inflammatory response initiated by microbial products signaling through Toll-like receptors (TLRs) of the innate immune system is essential for host defense against infection. Because inflammation can be harmful to host tissues, the innate response is highly regulated. Negative regulation of TLR4, the receptor for bacterial lipopolysaccharide (LPS), results in LPS tolerance, defined as hyporesponsiveness to repeated stimulation with LPS. LPS tolerance is thought to protect the host from excessive inflammation by turning off TLR4 signal, which then shuts down TLR-induced genes. However, TLR signaling induces hundreds of genes with very different functions. We reasoned that genes with different functions should have different requirements for regulation. Specifically, genes encoding proinflammatory mediators should be transiently inactivated to limit tissue damage, while genes encoding antimicrobial effectors, which directly target pathogens, should remain inducible in tolerant cells to protect the host from infection. Using an in vitro system of LPS tolerance in macrophages, here we show that TLR-induced genes may indeed be divided into two distinct categories based on their functions and regulatory requirements. Further, we show these distinct groups are regulated by gene-specific, and not signal-specific mechanisms. Experiment Overall Design: We examined gene expression using affymetrix genechips in 3 groups of murine bone-marrow derived macrophages: Naive (untreated), Naive stimulated with LPS, and Tolerant stimulated with LPS. Two biological replicates were performed for each group.

2008-06-15 | E-GEOD-7348 | biostudies-arrayexpress

Mitochondrial PGAM5−Drp1 signaling regulates the metabolic reprogramming of macrophages and regulates the induction of inflammatory responses

Project description:Macrophages play a critical role in the regulation of inflammation and tissue homeostasis. In addition to their vital functions for cell survival and physiology, mitochondria play a crucial role in innate immunity as a platform for the induction of inflammatory responses by regulating cell signaling and dynamics. Dynamin-related protein 1 (Drp1) plays a role in the induction of inflammatory responses and the subsequent development of various diseases. PGAM5 (phosphoglycerate mutase member 5) is a mitochondrial outer membrane phosphatase that dephosphorylates its substrate, Drp1. Previous studies showed that PGAM5 regulates the phosphorylation of Drp1 for the activation of NKT cells and T cells. However, it is not clear how PGAM5 regulates Drp1 activity for the induction of inflammation in macrophages. Here, we demonstrate that PGAM5 activity regulates the dephosphorylation of Drp1 in macrophages, leading to the induction of proinflammatory responses in macrophages. In TLR signaling, PGAM5 regulates the expression and production of inflammatory cytokines by regulating the activation of downstream signaling pathways, including the NF-kB and MAPK pathways. Upon LPS stimulation, PGAM5 interacts with Drp1 to form a complex, leading to the production of mtROS. Furthermore, PGAM5-Drp1 signaling promotes the polarization of macrophages toward a proinflammatory phenotype. Our study further demonstrates that PGAM5-Drp1 signaling promotes metabolic reprogramming by upregulating glycolysis and mitochondrial metabolism in macrophages. Altogether, PGAM5 signaling might be a link between alterations in Drp1-mediated mitochondrial dynamics and inflammatory responses in macrophages and may be a target for the treatment of inflammatory diseases.

2023-06-20 | GSE235306 | GEO

Gene Expression in Naive and Tolerant Macrophages stimulated with LPS

2007-04-22 | GSE7348 | GEO

Transcription profiling of mouse LPS-stimulated macrophages from wild-type and Zc3h12a-/- knockouts

Project description:Lipopolysaccharide (LPS), a Toll-like receptor (TLR) 4 ligand, induces the expression of various genes including proinflammatory cytokines, and the expression is modified by the presence of Zc3h12a. We used microarrays to examine influence of Zc3h12a deficiency in LPS-inducible gene expression. Experiment Overall Design: Peritoneal macrophages from wild-type and Zc3h12a-/- mice were stimulated with LPS for 0, 1, 2 and 4 hours, followed by RNA extraction. Then hybridization on affymetrix microarrays was performed.

2009-03-01 | E-GEOD-14891 | biostudies-arrayexpress

Carboplatin-mediated recovery of LPS-induced tolerant macrophages via H3K9me3 modifications

Project description:Following the re-exposure to lipopolysaccharide (LPS), macrophages exhibit the immunosuppressive state contribute to low production of proinflammatory cytokines and inability to respond the stimuli, a phenomenon is termed “tolerance”. Histone modification has been found in LPS-induced tolerant macrophages. Carboplatin, an antitumor drug, exerts its general effect on inhibition of DNA replication and transcription as well as epigenetic modification. Therefore, we hypothesized that carboplatin can be used to rescue the tolerance in macrophages. We found that carboplatin increases IL-6 but not TNF-α production in LPS-primed cells. The significant inductions were examined in carboplatin-treated tolerant macrophages evaluated by ELISA and qPCR. GSEA analyses revealed that p53 was the significant hallmark in both primed and tolerant RNA-Seq transcripts under carboplatin exposure while E2F ang G2/M were the upmost in negative hallmarks. HP1-α, heterochromatin protein 1, was significantly reduced in carboplatin-treated tolerant macrophages. The significant lower transcript of H3K9me3 methyltransferase, setdb2, was determined whereas kdm4d, demethylase encoding gene was significantly up-regulated in the presence of carboplatin in tolerant macrophages. Based on our data we suggested that carboplatin mediated upregulation of proinflammatory cytokine and rescue tolerance via the H3K9me3 modification. Carboplatin is potentially be a therapeutic drug for tolerance recovery in sepsis patients.

2021-11-10 | GSE179974 | GEO

Transcription profiling of mouse LPS-stimulated macrophages from wild-type, MyD88-/- and TRIF-/- animals

Project description:Lipopolysaccharide (LPS), a Toll-like receptor (TLR) 4 ligand, activates intracellular signaling via adaptors, MyD88 and TRIF, leading to the expression of various genes including proinflammatory cytokines. We used microarrays to examine influence of MyD88 or TRIF deficiency in LPS-inducible gene expression. Experiment Overall Design: Peritoneal macrophages from wild-type, MyD88-/- and TRIF-/- mice were stimulated with LPS for 0, 1 and 4 hours, followed by RNA extraction. Then hybridization on affymetrix microarrays was performed.

2009-03-01 | E-GEOD-14890 | biostudies-arrayexpress

LPS-induced gene expression in mouse small intestinal epithelial cells

Project description:Intestinal epithelial cells express the lipopolysaccharide (LPS) receptor Toll-like receptor (TLR4) and are responsive to LPS stimulation. Following LPS exposure, epithelial cells, similar to myeloid cells such as macrophages, acquire a state of tolerance. Innate immune tolerance is characterized by a lack of expression of proinflammatory genes in response to repeated stimulation. Tolerant epithelial cells, however, exhibit sustained expression of a distinct set of genes encoding for proteins involved in metabolism and homeostasis. This study comparatively analyzes the gene expression profile 6 hours after LPS stimulation (acute response) versus 6 hours LPS followed by 90 hours incubation in the absence of LPS (tolerant response). We used microarrays to detail the global program of gene expression under unstimulated (control), LPS stimulated (6 hours), and tolerant (96 hours) conditions. Three biological replicates each from naive cells, 6 hour LPS-stimulated cells, and 6 hour LPS-stimulated plus 90 hour LPS-free medium-incubated cells were examined and compared.

2010-08-29 | E-GEOD-23755 | biostudies-arrayexpress

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