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Targeting macrophage M1 polarization suppression through PCAF inhibition alleviates autoimmune arthritis via synergistic NF-κB and H3K9Ac blockade

ABSTRACT: Targeting macrophage M1 polarization suppression through PCAF inhibition alleviates autoimmune arthritis via synergistic NF-κB and H3K9Ac blockade

PROVIDER: PRJNA912567 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22746216_1.fastq.gz	Fastqsanger.gz
	SRR22746216_2.fastq.gz	Fastqsanger.gz
	SRR22746217_1.fastq.gz	Fastqsanger.gz
	SRR22746217_2.fastq.gz	Fastqsanger.gz
	SRR22746218_1.fastq.gz	Fastqsanger.gz

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Targeting macrophage M1 polarization suppression through PCAF inhibition alleviates autoimmune arthritis via synergistic NF-κB and H3K9Ac blockade

Project description:M1 macrophages are considered to contribute to autoimmune arthritis such as rheumatoid arthritis, spondyloarthritis. However, the exact role of M1 macrophage during inflammatory joint disease remain unclear. To explore the molecular mechanisms underlying M1 macrophage in autoimmune arthritis, we performed the whole transcriptome sequencing of 3 repeats of M0, 3 repeats of M1 without 20 μM Garcinol and 3 repeats of M1 with 20 μM Garcinol.

2022-12-20 | GSE221012 | GEO

Targeting macrophage M1 polarization suppression through PCAF inhibition alleviates autoimmune arthritis via synergistic NF-κB and H3K9Ac blockade.

Project description:Sustained inflammatory invasion leads to joint damage and progressive disability in several autoimmune rheumatic diseases. In recent decades, targeting M1 macrophage polarization has been suggested as a promising therapeutic strategy for autoimmune arthritis. P300/CBP-associated factor (PCAF) is a histone acetyltransferase (HAT) that exhibits a strong positive relationship with the proinflammatory microenvironment. However, whether PCAF mediates M1 macrophage polarization remains poorly studied, and whether targeting PCAF can protect against autoimmune arthritis in vivo remains unclear. Commonly used drugs can cause serious side effects in patients because of their extensive and nonspecific distribution in the human body. One strategy for overcoming this challenge is to develop drug nanocarriers that target the drug to desirable regions and reduce the fraction of drug that reaches undesirable targets. In this study, we demonstrated that PCAF inhibition could effectively inhibit M1 polarization and alleviate arthritis in mice with collagen-induced arthritis (CIA) via synergistic NF-κB and H3K9Ac blockade. We further designed dextran sulfate (DS)-based nanoparticles (DSNPs) carrying garcinol (a PCAF inhibitor) to specifically target M1 macrophages in inflamed joints of the CIA mouse model via SR-A-SR-A ligand interactions. Compared to free garcinol, garcinol-loaded DSNPs selectively targeted M1 macrophages in inflamed joints and significantly improved therapeutic efficacy in vivo. In summary, our study indicates that targeted PCAF inhibition with nanoparticles might be a promising strategy for treating autoimmune arthritis via M1 macrophage polarization inhibition.

| S-EPMC10439630 | biostudies-literature

High-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) Protects Against Ischemic Stroke by Inhibiting M1 Microglia Polarization through Let-7b-5p/HMGA2/NF-κB Signaling Pathway

Project description:Modulating M1/M2 polarization is a potential therapy for treating ischemic stroke. Repetitive transcranial magnetic stimulation (rTMS) held the capacity to regulate astrocytic polarization, but little is known about rTMS effects on microglia. Therefore, the present study aimed to investigate whether and how rTMS influence microglia polarization in ischemic stroke models. The 10-Hz rTMS was applied to transient middle cerebral artery occlusion (MCAO) rats and oxygen and glucose deprivation/ reoxygenation injured BV2 cells. Western blot, immunofluorescence and ELISA were used to detect M1/M2 markers. High-throughput sequencing, RT-PCR and FISH staining were adopted to test microRNA changes. The 10-Hz rTMS inhibited ischemia/reperfusion induced M1 microglia and significantly increased let-7b-5p. HMGA2 was proved to be the target protein of let-7b-5p and its downstream NF-κB signaling pathway were inhibited by rTMS. Microglia culture medium (MCM) collected from rTMS treated microglia had low TNF-α but high IL-10 concentration, leading to reduced neural death, minor ischemic volumes and improved functional recovery of MCAO animals. However, knockdown of let-7b-5p by antagomir reversed rTMS effects on microglia. In conclusion, high-frequency rTMS could improve functional recovery through inhibiting M1 microglia polarization via regulating let-7b-5p/HMGA2/NF-κB signaling pathway in cerebral ischemic stroke models.

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M1 macrophages induce an inflammatory phenotype in melanoma cells via TNFR-NF-κB signaling

Project description:Tumor microenvironment with distinctive cell types and a complex extracellular matrix has a tremendous effect on cancer progression. In the present study we investigated the effects of proinflammatory (M1) and immunosuppressive (M2) macrophages on melanoma cell hyaluronan (HA) metabolism and inflammatory response. M1 macrophages stimulated the formation of a thick pericellular HA matrix in melanoma cells, and the overall HA synthesis was increased due to upregulation of HA synthases (HAS) 1 and 2. HAS2 silencing reversed the effect of M1 CM (conditioned medium) on pericellular HA coat formation, similarly as the chemical inhibitors for TNFR (R-7050), IKK2 (IKK16) and MEK (U0126). RNA sequencing analysis indicated that several inflammation related genes (IL1, IL6, CXCL6) were highly upregulated in M1 CM treated melanoma cells. Gene set enrichment analysis identified that genes related to inflammatory response and TNFα signaling via NF-κB are enriched in M1 CM treated cells. Our results indicate that the activation of MEK and TNFR-NF-κB signaling leads to HAS2 upregulation, while MEK signaling pathway is not involved in cytokine upregulation. Furthermore, HAS2 silencing downmodulated the M1 CM-induced cytokine expression. Our results indicate that proinflammatory macrophages induce an inflammatory response in melanoma cells, where HAS2 upregulation associates with a protumor inflammatory gene signature.

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Gcn5 and PCAF negatively regulate interferon β production through HAT-independent inhibition of TBK1 [RNA-Seq]

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Gcn5 and PCAF negatively regulate interferon β production through HAT-independent inhibition of TBK1 [ChIP-Seq]

Project description:Gcn5/PCAF dobule knockout (dKO) in MEFs leads to loss of the global H3K9ac, but only affect expression of a small nubmer of genes according to RNA-Seq data. To examine the function of H3K9ac on gene activation, H3K9ac ChIP-Seq was performed. We found that H3K9ac at Transcriptional Start sites (TSSs) of no-changed, up-regulated and down-regulated genes are all dramatially decreased in Gcn5/PCAF dKO cells, suggesting that H3K9ac is largely not required for gene activation. PCAF-/-;Gcn5f/D MEFs were infected with retroviral Cre to delete Gcn5 to generate Gcn5/PCAF dKO cells, followed by H3K9ac ChIP-Seq analysis

2014-09-03 | E-GEOD-60967 | biostudies-arrayexpress

TPPU alleviate cartilage degradation in temporomandibular joint osteoarthritis by inhibiting M1 macrophage polarization through the EETs/IL-17/NF-KB signaling pathway

Project description:In the treatment of inflammatory diseases, TPPU has shown potential therapeutic effects on a variety of inflammatory conditions, including reshaping the body's pro-inflammatory/anti-inflammatory balance by stabilizing endogenous anti-inflammatory substances EETs. In cardiovascular diseases, TPPU can regulate the NF-κB signaling pathway to modulate macrophage polarization and reduce inflammation. To explore the mechanism of TPPU in regulating M1 macrophages in TMJOA, we treated M1 macrophages with TPPU. In short, we attempted to verify the key signaling molecules and pathways regulated by TPPU in M1 macrophages.

2025-01-01 | GSE285011 | GEO

Myeloid cell derived inducible nitric oxide synthase suppresses M1 macrophage polarization

Project description:Analysis of gene expression between WT and iNOS defecient M1 macrophage RNA microarray was performed using RNA isolated from M1 polarized macrophages from WT and iNOS deficient mice stimulated with LPS/IFNγ for 6 hours. Total RNA was extracted using a RNeasy plus kit (QIAGEN, Valencia, CA), and the array was performed on an Illumina MouseRef-8 v2.0 expression beadchip (Illumina, USA) by the Genomics Core Facility at the Mount Sinai School of Medicine.

2015-02-02 | E-GEOD-65436 | biostudies-arrayexpress

Gcn5 and PCAF negatively regulate interferon β production through HAT-independent inhibition of TBK1 [RNA-Seq]

Project description:Gcn5/PCAF double knockout (dKO) leads to loss of the global H3K9ac. RNA-Seq was performed to define the changes of gene expression in response to Gcn5/PCAF deletion and H3K9ac loss PCAF-/-;Gcn5f/D MEFs were infected with retroviral Cre to delete Gcn5 to generate Gcn5/PCAF dKO cells, followed by RNA-Seq analysis using spike-in RNA as controls

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Gcn5 and PCAF negatively regulate interferon β production through HAT-independent inhibition of TBK1 [ChIP-Seq]

2014-09-03 | GSE60967 | GEO