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M6A RNA methylation mediates NOD1/NF-kB signaling activation in the liver of piglets challenged with lipopolysaccharide

ABSTRACT: N6-methyladenosine (m6A) is the most abundant internal modification that widely participates in various immune and inflammatory responses, however, its regulatory mechanisms in the inflam-mation of liver induced by lipopolysaccharide in piglets remain largely unknown. In the present study, MeRIP-seq showed that 1166 and 1344 transcripts contained m6A methylation in control and LPS groups, respectively. The m6A methylation sites of these transcripts mainly distributes in the 5’ un-translated region (5’UTR), the coding sequence (CDS), and the 3’ untranslated region (3’UTR). In-terestingly, these genes were mostly enriched in the NF-κB signaling pathway, and LPS treatment significantly changed the m6A modification among NOD1, RIPK2, NFKBIA, NFKBIB and TNFAIP3 mRNAs.In conclusion, LPS activated the NOD1/NF-κB pathway at post-transcriptional regulation through changing m6A RNA methylation, and then promoted the overproduction of proinflammatory cytokines, ultimately resulting in liver inflammation and damage.

ORGANISM(S): Sus scrofa

PROVIDER: GSE209858 | GEO | 2022/10/06

REPOSITORIES: GEO

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Genipin inhibits LPS-induced acute systemic inflammation in mice

Project description:Genipin is a natural blue colorant in food industry. Inflammation is correlated with human disorders, and nuclear factor-κB (NF-κB) is the critical molecule involved in inflammation. In this study, the anti-inflammatory effect of genipin on the lipopolysaccharide (LPS)-induced acute systemic inflammation in mice was evaluated by NF-κB bioluminescence-guided transcriptomic analysis. Transgenic mice carrying the NF-κB-driven luciferase genes were administered intraperitoneally with LPS and various amounts of genipin. Bioluminescent imaging showed that genipin significantly suppressed LPS-induced NF-κB-dependent luminescence in vivo. The suppression of LPS-induced acute inflammation by genipin was further evidenced by the reductions of cytokine levels in sera and organs. Microarray analysis of these organs showed that the transcripts of 79 genes were differentially expressed in both LPS and LPS/genipin groups, and one third of these genes belonged to chemokine ligand, chemokine receptor, and interferon (IFN)-induced protein genes. Moreover, network analysis showed that NF-κB played a critical role in the regulation of genipin-affected gene expression. In conclusion, we newly identified that genipin exhibited anti-inflammatory effects in a model of LPSinduced acute systemic inflammation via downregulation of chemokine ligand, chemokine receptor, and IFN-induced protein productions. A total of 25 transgenic mice (female, 6 to 8 weeks old) were randomly divided into five groups of five mice: (1) mock, no treatment; (2) LPS (4 mg/kg), (3) LPS plus genipin (1 mg/kg), (4) LPS plus genipin (10 mg/kg), and (5) LPS plus genipin (100 mg/kg). Mice were challenged intraperitoneally with LPS and then with genipin 10 min later. Four hours later, mice were imaged for the luciferase activity, and subsequently sacrificed for ex vivo imaging, RNA extraction, and immunohistochemical staining.

2012-02-25 | E-GEOD-35934 | biostudies-arrayexpress

METTL3 Regulates LPS-Induced Inflammatory Response via the NOD1 Signaling Pathway

Project description:Inflammation is normally a protective response to defend and restore homeostasis; nonresolving inflammation is a major driver of immune disorders. N6-methyladenosine (m6A) is a prevalent mRNA modification that plays a crucial function in multiple biological processes. The effect of m6A on the immune response has recently been reported. However, the effect is unclear, and the results are contradictory. In this study, the expression of total m6A and the methyltransferase METTL3 decreased in LPS-stimulated macrophages. METTL3 knockdown significantly upregulated expression of proinflammatory cytokines, including TNF-α, IL-6 and NO. RNA sequencing analysis showed that the upregulated genes were enriched in inflammation-related signaling pathways and that the NOD-like receptor signaling pathway might be the target molecules of METTL3. METTL3 depletion resulted in upregulation of the NOD1 pathway without impacting NOD2. Moreover, the increase in proinflammatory cytokines induced by METTL3 knockdown was reversed by blocking the NOD1 pathway using the NOD-IN-1 and ML130 specific inhibitors. Mechanistically, METTL3 knockdown promoted the mRNA expression and stability of NOD1 and RIPK2, and the same results were detected in m6A-binding protein YTHDF1- or YTHDF2-silenced cells. All findings suggested that METTL3 depletion inhibits the degradation of NOD1 and RIPK2 mRNA mediated by YTHDF1 and YTHDF2, which upregulate the NOD1 pathway and subsequently promote the LPS-induced inflammatory response in macrophages.

2022-06-01 | GSE189412 | GEO

Genipin inhibits LPS-induced acute systemic inflammation in mice

2012-02-25 | GSE35934 | GEO

Immune surveillance of cellular homeostasis by NOD1/2 via sensing cytosolic sphingosine-1-phosphate (S1P)

Project description:Chronic inflammation is associated with disruption of cellular homeostasis, yet the underlying mechanisms remain elusive1. Nucleotide-binding oligomerization domain-containing protein 1/2 (NOD1/2) are intracellular pathogen recognition receptors that activate innate immune responses via sensing bacterial peptidoglycans2-4. We demonstrate that NOD1/2 sense not only microbe-specific molecular patterns but also perturbation of cell homeostasis, and thereby cause inflammation. Host generation of sphingosine-1-phosphate (S1P) via the hydrolysis pathway is essential for NOD1/2 signaling upon such stress. Cytosolic delivery of S1P activates NOD1/2 dependent NF-κB activation and inflammation. Finally, we demonstrate that S1P directly binds to and activates NOD1/2. In sum, we describe a hitherto unknown role of NOD1/2 by revealing that they initiate innate immune responses by surveillance of cellular homeostasis through sensing of cytosolic S1P. Our findings provide a novel link between host cytosolic S1P and NOD1/2 mediated immune activation upon perturbation of cellular homeostasis and thus form the basis for future intervention strategies targeting the S1P-NOD1/2 axis.

2020-01-01 | GSE124828 | GEO

Genome-wide analysis of macrophage gene expression upon Bcl3 knockdown

Project description:By binding to specific DNA elements, known collectively as “κB sites”, contained within the promoters/enhancers of target genes, NF-κB regulates gene expression. We found that the identity of the central base pair (bp) of κB sites profoundly impacts the transcriptional activity of NF-κB dimers. RelA dimers prefer an A/T bp at this position for optimum transcriptional activation (A/T-centric) and discriminate against G/C-centric κB sites. The p52 homodimer, in contrast, activates transcription from G/C-centric κB sites in complex with Bcl3 but represses transcription from the A/T-centric sites. The p52:Bcl3 complex binds to these two classes of κB sites in distinct modes permitting recruitment of coactivator, corepressor, or both coactivator and corepressor complexes in promoters containing G/C, A/T or both G/C and A/T-centric sites. Therefore, through sensing of bp differences within κB sites, NF-κB dimers modulate biological programs by activating, repressing and altering expression of effector genes. Total RNA extracted from bone marrow derived macrophages (BMDMs) with Bcl3 siRNA knockdown or mouse scramble siRNA knockdown were subjected to LPS stimulation.

2012-08-06 | E-GEOD-39922 | biostudies-arrayexpress

m6A sequencing analysis of chicken hepatic mRNA under normal and LPS stimulated conditions

Project description:Here, the m6A modification patterns in chicken liver at the acute stage of LPS-stimulated inflammation and at the normal state were explored via m6A and RNA sequencing and bioinformatics analysis. A total of 7815 m6A peaks distributed in 5066 genes were identified in the normal chicken liver, and were mostly located in the CDS, 3’UTR region and around the stop codon. At 2 h after the LPS intraperitoneal injection, the m6A modification pattern changed, and showed 1200 different m6A peaks. The hyper- and hypo-m6A peaks were differentially located, with the former mostly located in the CDS region and the later in the 3’UTR and in the region near the stop codon. The hyper- or hypo methylated genes were enriched in different GO ontrology and pathways. Co-analysis revealed a significantly positive relationship between the fold change of m6A methylation level and the relative fold change of mRNA expression. Moreover, protein and protein interaction analysis showed that genes with altered m6A methylation and mRNA expression levels were clustered in processes involved in lipid metabolism, immune response, DNA replication and protein ubiquitination. CD18 and SREBP-1 were the two hub genes clustered in the immune process and lipid metabolism, respectively. Hub gene AGPAT2 was suggested to link the immune response and lipid metabolism clusters in the PPI network. This study presented the first m6A map of broiler chicken liver at the acute stage of LPS induced inflammation. The findings may shed lights on the possible mechanisms of m6A-mediated lipid metabolism disorder in inflammation.

2022-11-24 | GSE189591 | GEO

Genome wide analysis of HDL and cyclodextrin induced gene expression in LPS-stimulated bone marrow derived macrophages

Project description:While LPS as expected induced a strongly upregulatedion of pro-inflammatory genes and signaling pathways, HDL and cyclodextrin clearly enhanced LPS-induced signaling, especially of Interferon Regulatory Factor (IRF)1 and Nuclear Factor-κB (NF-κB)-p65 dependent genes

2016-11-17 | GSE70155 | GEO

Novel anti-inflammatory activity of chlorojanerin isolated from Sausurrea heteromalla (D. Don) Hand.-Mazz.

Project description:Medicinal plants have shown great promise as a source of novel drug compounds for the treatment of inflammatory disorders. In our search for new entities with anti-inflammatory potential, the extracts of the whole plant of Saussurea heteromalla (family-Asteraceae), collected from Himalayas, were evaluated in the high throughput screen for TNF-α and IL-6 inhibitors. The plant has been found as a new source of chlorojanerin, a guaianolide type of sesquiterpene lactone. This is the first report on the potent anti-inflammatory activity of the compound. Chlorojanerin was shown to be significantly effective in inhibiting TNF-α and IL-6 production in LPS induced THP-1 cells (TNF-α, IC50 = 3µM and IL-6, IC50 = 0.8µM). The compound also blocked TNF-α and IL-6 production from LPS induced human monocytes and synovial cells from RA patients. Chlorojanerin also inhibited the binding of NF-κB in a GFP reporter assay system. Transcriptional profiling of the LPS stimulated THP-1 cells revealed that chlorojanerin exerted its anti-inflammatory effect by inhibiting the expression of genes involved in activating the transcription factor – NF-κB. Real time analysis of these genes validated the effect of chlorojanerin on the classical downstream targets of NF-κB. Thus, this study clearly delineated 8 targets specific for the effect of chlorojanerin on NF-κB induced signaling at the mRNA level. This work is a step towards the isolation and characterization of lead anti-inflammatory agents from the extract of Saussurea heteromalla, which can be developed into better therapeutic molecules targeted towards some specific inflammatory diseases. Single dye labelling with Cy3 for all treatment RNA samples. Treatments included unstimulated, LPS stimulated, Chlorjanerin treatment and dexamethasone treatment.

2011-12-14 | E-GEOD-34180 | biostudies-arrayexpress

MeRIP-seq for microglia treated with PBS or LPS

Project description:The experiment is to demonstrate the global m6A methylation signatures and their correlation with mRNA expression patterns in microglia stimulated by LPS. The results also identified m6A modifiers with significantly altered expression, which reveals the key one that regulate the m6A modifications in microglia.

2022-12-31 | E-MTAB-11568 | biostudies-arrayexpress

Distinct N6-methyladenosine (m6A) Regulation of Innate Immune Responses During Bacterial and Viral Infections I

Project description:N6-methyladenosine (m6A) is a dynamic post-transcriptional RNA modification influencing all aspects of mRNA biology. Here, we examined cellular m6A epitranscriptomes during infections of herpes simplex virus type 1 (HSV-1) and lipopolysaccharide (LPS) stimulation to identify m6A-regulated innate immune response genes. We showed that a significant portion of cellular genes including many innate immune response genes underwent m6A modifications in 5’UTR and 3’UTR, from which we identified common and distinct m6A-modified genes under different stimulating conditions.

2022-03-21 | GSE196269 | GEO

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