Self-assembled hyaluronic acid nanoparticles target TLR2 to regulate macrophage M1 polarization and alleviate psoriasis
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PROVIDER: PRJNA1159773 | ENA |
REPOSITORIES: ENA
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Project description:Self-assembled hyaluronic acid nanoparticles (HANPs) possess unique biocompatibility and receptor-binding properties, making them widely studied as drug delivery systems. Notably, empty HANPs alone have demonstrated therapeutic and ameliorative effects in various inflammatory diseases. In this study, we conjugated hyaluronic acid and 5βcholanic acid to create self-assembled nanoparticles (HACNs). We then investigated the effects of HACNs on macrophage polarization towards the pro-inflammatory M1 phenotype using mouse primary bone marrow-derived macrophages and the human monocyte cell line THP-1 cells. Our findings reveal that HACNs directly interact with Toll-like receptor 2 (TLR2) and effectively suppress the expression of pro-inflammatory mediators by competitively inhibiting ligand-receptor interactions in macrophages. This inhibitory effect on TLR2 signaling is mainly due to the spherical structure of the selfassembled hydrophilic hyaluronic acid (HA) shell, rather than to free HA or the hydrophobic core component, 5β-cholanic acid. Furthermore, the protective effects of HACNs against IMQ-induced epidermal hyperplasia and elevated pro-inflammatory cytokine levels were significantly diminished in TLR2-defecient mice. These results highlight the potential of empty HACNs as effective therapeutic agents for TLR2- mediated inflammatory disorders.
2025-09-11 | GSE276941 | GEO
Project description:Hyaluronic acid was proposed to support soft tissue recession surgery and guided tissue regeneration. Nevertheless, the molecular mechanisms through which hyaluronic acid modulates the response of the connective tissue cells remain elusive. To elucidate the impact of hyaluronic acid on the connective tissue cells, we employed bulk RNA sequencing to unravel the changes in the genetic signature gingival fibroblasts exposed to 1.6% cross-linked hyaluronic acid and 0.2% natural hyaluronic acid hyaluronic acid. Transcriptome-wide changes were modest, even when implementing a minimum of 1.5 log2 fold-change and a significance threshold of 1.0 -log10; only a dozenth gene was differentially expressed and ranked according to the Manhattan distance. Upregulated were PLK3, SLC16A6, IL6, HBEGF, DGKE, DUSP4, PTGS2, FOXC2, ATAD2B, NFATC2, and downregulated were MMP24 and PLXNA2. RT-PCR analysis supported the impact of hyaluronic acid on increasing expression of the selected gene panel. The findings from bulk RNA sequencing suggest that gingival fibroblasts only show a weak response when exposed to hyaluronic acid.
2025-09-09 | GSE279587 | GEO
Project description:Toll-like receptor 2 (TLR2) is a pattern recognition receptor that, upon ligation by microbial molecules, interacts with other proteins to initiate pro-inflammatory responses by the cell. Statins (hydroxymethylglutaryl coenzyme A reductase inhibitors), drugs widely prescribed to reduce hypercholesterolemia, are reported to have both pro- and anti-inflammatory effects upon cells. Some of these responses are presumed to be driven by effects on signaling proteins at the plasma membrane, but the underlying mechanisms remain obscure. We reasoned that profiling the effect of statins on the repertoire of TLR2-interacting proteins might provide novel insights into the mechanisms by which statins impact inflammation. In order to study the TLR2 interactome, we designed a co-immunoprecipitation (IP)-based cross-linking proteomics study. A hemagglutinin (HA)-tagged-TLR2 transfected HEK293 cell line was utilized to precipitate the TLR2 interactome upon cell exposure to the TLR2 agonist Pam3CSK4 and simvastatin, singly and in combination. To stabilize protein interactors, we utilized two different chemical cross-linkers with different spacer chain lengths. Proteomic analysis revealed important combinatorial effects of simvastatin and Pam3CSK4 on the TLR2 interactome. After stringent data filtering, we identified alpha-centractin (ACTR1A), an actin-related protein and subunit of the dynactin complex, as a potential interactor of TLR2. The interaction was validated using biochemical methods. RNA interference studies revealed an important role for ACTR1A in induction of pro-inflammatory cytokines. Taken together, we report that statins remodel the TLR2 interactome, and we identify ACTR1A, a part of the dynactin complex, as a novel regulator of TLR2-mediated immune signaling pathways.
2019-06-24 | PXD012759 | Pride
Project description:Both sulfated hyaluronic acid and dexamethasone are candidates for the functionalization of bone grafts as they were shown to enhance the differentiation of osteoblasts from bone marrow stromal cells in vitro and in vivo. However, the underlying mechanisms are not fully understood. Furthermore, studies combining different approaches to assess to synergistic potentials are rare. In this study, we aim gain insights into the mode-of-action of both sulfated hyaluronic acid and dexamethasone by a comprehensive analysis of the cellular fraction, released matrix vesicles and the extracellular matrix, combining classical biochemical assays with mass spectrometry-based proteomics and further supported by novel bioinformatical computation.
2019-03-15 | PXD009434 | Pride
Project description:Acetaminophen (N-acetyl-p-aminophenol, APAP) is a common antipyretic agent and analgesic. An overdose of APAP can result in acute liver injury (ALI). Oxidative stress and inflammation are central to liver injury. N-acetylcysteine (NAC), a precursor of glutathione, is used commonly in clinical settings. However, the window of NAC treatment is limited, and more efficacious alternatives must be found. Endogenous cytokines such as fibroblast growth factor (FGF) 21 can improve mitochondrial function while decreasing intracellular oxidative stress and inflammatory responses, thereby exhibiting antioxidant-like effects. In this study, self-assembled nanoparticles comprising chitosan and heparin (CH) were developed to deliver FGF21 (CH-FGF21) to achieve the sustained release of FGF21 and optimize the in vivo distribution of FGF21. CH-FGF21 attenuated the oxidative damage and intracellular inflammation caused by APAP to hepatocytes effectively. In a murine model of APAP-induced hepatotoxicity, CH-FGF21 could alleviate ALI progression and promote the recovery of liver function. These findings demonstrated that a simple assembly of CH nanoparticles carrying FGF21 could be applied for the treatment of liver diseases.
| S-EPMC9871310 | biostudies-literature
Project description:In the present study, RNA-seq were performed To identify clinical relevance of PLAUR, a putative Serpin E1 receptor, in cutaneous itch signaling and crosstalk pathways with other critical itch modulators.mRNA profiles were generated by deep sequencing, in triplicate, using MGISEQ-2000. Our experiment showed Serpin E1-treatment further led to a marked upregulation of TLR2 transcript in mDRG neurons, along with enhanced transcription of cosignaling proteins belonging to pro-inflammatory signaling pathways including NF-κB signaling proteins. We next investigated the consequence of TLR2 activation in mTGNs using the TLR agonists, Pam3CSK4 (TLR1/2 agonist), FSL-1 (TLR2/6 agonist), or vehicle. Among these transcripts, TLR2 was found upregulated strongest by both TLR2 agonists suggesting a selfenhancing feedback loop of TLR2 activation.The PLAUR-TLR2 axis promotes cutaneous inflammation and itch, both feeding into an aggravation of AD. This finding might help us to better understand the skin-nerve communication in itch circuits.
2022-08-03 | GSE189333 | GEO
Project description:The interaction between monocytes and endothelial cells in inflammation is central to chemoattraction, adhesion, and transendothelial migration. Key players such as selectins and their ligands, integrins and other adhesion molecules and their function in these processes are well studied. Toll-like receptor 2 (TLR2), expressed on monocytes, is critical for sensing invading pathogens and initiating a rapid and effective immune response. However, the extended role of TLR2 in monocyte adhesion and migration has only been partially elucidated. To address this question, we performed several functional cell-based assays using monocyte-like wild type (WT), TLR2-knock-out (KO) and, TLR2-knock-in (KI) THP-1 cells. We found that TLR2 promotes faster and stronger adhesion of monocytes to the endothelium and a more intense endothelial barrier disruption after endothelial activation. In addition, we performed quantitative mass-spectrometry, STRING protein analysis, and RT-qPCR, which revealed the association of TLR2 with specific integrins, but also uncovered novel proteins affected by TLR2. In conclusion, we could show that unstimulated TLR2 affects cell adhesion, endothelial barrier disruption, migration, and actin polymerization.
2023-10-24 | PXD041819 | Pride
Project description:The activation of TLR-MyD88 (Toll like receptor- Myeloid differentiation factor 88) signaling within T cells functions as a potent costimulatory signal that boosts antitumor and antiviral responses. However, the molecular mechanisms underlying the costimulatory processes are poorly understood. We compared microarray gene analysis data between TLR1-TLR2 stimulated and unstimulated T cell receptor transgenic ‘pmel’ and MyD88-/-pmel CD8+ T cells and identified changes in the expression levels of several TNF family members. In particular, TLR-stimulation increased 4-1BB levels in pmel but not in MyD88-/-pmel T cells. A link between 4-1BB and TLR1-TLR2 signaling in CD8+ T cells was highlighted by in fact that 4-1BB-/- T cells exhibited suboptimal responses to TLR1-TLR2 agonist, but responded normally to CD28 or OX40 costimulation. Moreover, blocking 4-1BB signaling with antibodies also hindered the costimulatory effects of the TLR1-TLR2 agonist. The elevated levels of 4-1BB transcripts in TLR1-TLR2–stimulated cells were not due to increased mRNA stability nor increased histone activation but instead were associated with increased binding of p65 and c-Jun to two distinct 4-1BB promoter sites. Combining TLR1-TLR2 ligand with an agonistic anti-4-1BB antibody enhanced the antitumor activity in mice with established melanoma tumors. These studies reveal that the costimulatory effects of TLR1-TLR2 signaling in CD8+ T cells are in part mediated by 4-1BB and are important for mounting an effective antitumor immune response.
2016-06-14 | GSE79475 | GEO
Project description:The vascular endothelium is integrally involved in the host response to infection and in organ failure during acute inflammatory disorders such as sepsis. Gram-negative and gram-positive bacterial lipoproteins circulate in sepsis and can directly activate the endothelium by binding to endothelial cell (EC) Toll-like receptor 2 (TLR2). In this report, we perform the most comprehensive analysis to date of the immune-related genes regulated after activation of endothelial TLR2 by bacterial di- and triacylated lipopeptides. We found that TLR2 activation specifically induces the expression of IL6, IL8, CSF2, CSF3, ICAM1 and SELE by human umbilical vein ECs and human lung microvascular ECs. These proteins participate in neutrophil recruitment, adherence and activation at sites of inflammation. Significantly, our studies demonstrate that bacterial lipopeptides activate human EC exclusively through TLR2, that TLR2-mediated EC responses are specifically geared towards recruitment, activation, and survival of neutrophils and not mononuclear leukocytes, and that ECs do not require priming by other inflammatory stimuli to respond to bacterial lipopeptides. This study suggests that endothelial TLR2 may be an important regulator of neutrophil trafficking to sites of infection in general, and that direct activation of lung endothelial TLR2 may contribute to acute lung injury during sepsis.
2011-06-23 | GSE30117 | GEO
Project description:In murine glioma models, TLR2 is selectively upregulated in glioma-associated microglia. We found that TLR2 activation led to down-regulation of MHC-II in microglia. Therefore, we examined the effect of TLR2 activation on IFN-gamma-induced microglial transcriptome by in vitro culture of murine adult microglia. In the study, we confirmed that TLR2 activation led to Ciita shutdown and inhibition of MHC-II related genes, which also revealed the role of TLR2 in inducing APC disability and tumor immune escape. In addition, this work can be used to reveal the transcriptional characteristics of murine microglia during IFN-gamma and TLR2 activation.
2018-09-25 | GSE109297 | GEO