scholarly journals TLR3 Ligand Poly(I:C) Exerts Distinct Actions in Synovial Fibroblasts When Delivered by Extracellular Vesicles

2018 ◽  
Vol 9 ◽  
Author(s):  
Mojca Frank-Bertoncelj ◽  
David S. Pisetsky ◽  
Christoph Kolling ◽  
Beat A. Michel ◽  
Renate E. Gay ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Synovial Fibroblasts ◽  
Poly I:C ◽  
Tlr3 Ligand Poly

scholarly journals Cell Interplay in Osteoarthritis

2021 ◽  
Vol 9 ◽  
Author(s):  
Zihao Li ◽  
Ziyu Huang ◽  
Lunhao Bai
Keyword(s):  
Stem Cells ◽  
Extracellular Vesicles ◽  
Therapeutic Potential ◽  
Cell Communication ◽  
Synovial Fibroblasts ◽  
Health Concern ◽  
Common Chronic Disease ◽  
Cell Tissue ◽  
Induced Pluripotent

Osteoarthritis (OA) is a common chronic disease and a significant health concern that needs to be urgently solved. OA affects the cartilage and entire joint tissues, including the subchondral bone, synovium, and infrapatellar fat pads. The physiological and pathological changes in these tissues affect the occurrence and development of OA. Understanding complex crosstalk among different joint tissues and their roles in OA initiation and progression is critical in elucidating the pathogenic mechanism of OA. In this review, we begin with an overview of the role of chondrocytes, synovial cells (synovial fibroblasts and macrophages), mast cells, osteoblasts, osteoclasts, various stem cells, and engineered cells (induced pluripotent stem cells) in OA pathogenesis. Then, we discuss the various mechanisms by which these cells communicate, including paracrine signaling, local microenvironment, co-culture, extracellular vesicles (exosomes), and cell tissue engineering. We particularly focus on the therapeutic potential and clinical applications of stem cell-derived extracellular vesicles, which serve as modulators of cell-to-cell communication, in the field of regenerative medicine, such as cartilage repair. Finally, the challenges and limitations related to exosome-based treatment for OA are discussed. This article provides a comprehensive summary of key cells that might be targets of future therapies for OA.

scholarly journals ZCCHC3 modulates TLR3-mediated signaling by promoting recruitment of TRIF to TLR3

2020 ◽  
Vol 12 (4) ◽  
pp. 251-262
Author(s):  
Ru Zang ◽  
Huan Lian ◽  
Xuan Zhong ◽  
Qing Yang ◽  
Hong-Bing Shu
Keyword(s):  
Rna Virus ◽  
Interleukin 1 ◽  
Innate Immune ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Antiviral Genes ◽  
Ligand Stimulation ◽  
Tlr3 Ligand Poly ◽  
Receptor Domain

Abstract Toll-like receptor 3 (TLR3)-mediated signaling is important for host defense against RNA virus. Upon viral RNA stimulation, toll and interleukin-1 receptor domain-containing adaptor inducing IFN-β (TRIF) is recruited to TLR3 and then undergoes oligomerization, which is required for the recruitment of downstream molecules to transmit signals. Here, we identified zinc finger CCHC-type containing 3 (ZCCHC3) as a positive regulator of TLR3-mediated signaling. Overexpression of ZCCHC3 promoted transcription of downstream antiviral genes stimulated by the synthetic TLR3 ligand poly(I:C). ZCCHC3-deficiency markedly inhibited TLR3- but not TLR4-mediated induction of type I interferons (IFNs) and proinflammatory cytokines. Zcchc3−/− mice were more resistant to poly(I:C)- but not lipopolysaccharide-induced inflammatory death. Mechanistically, ZCCHC3 promoted recruitment of TRIF to TLR3 after poly(I:C) stimulation. Our findings reveal that ZCCHC3 plays an important role in TLR3-mediated innate immune response by promoting the recruitment of TRIF to TLR3 after ligand stimulation.

scholarly journals Receptor-interacting protein kinase 1 is a key mediator in TLR3 ligand and Smac mimetic-induced cell death and suppresses TLR3 ligand-promoted invasion in cholangiocarcinoma

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Thanpisit Lomphithak ◽  
Swati Choksi ◽  
Apiwat Mutirangura ◽  
Rutaiwan Tohtong ◽  
Tewin Tencomnao ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Cell Lines ◽  
Mapk Signaling ◽  
Poly I:C ◽  
Interacting Protein ◽  
Smac Mimetic ◽  
Tlr3 Signaling ◽  
Tlr3 Ligand Poly

Abstract Background Toll-like receptor 3 (TLR3) ligand which activates TLR3 signaling induces both cancer cell death and activates anti-tumor immunity. However, TLR3 signaling can also harbor pro-tumorigenic consequences. Therefore, we examined the status of TLR3 in cholangiocarcinoma (CCA) cases to better understand TLR3 signaling and explore the potential therapeutic target in CCA. Methods The expression of TLR3 and receptor-interacting protein kinase 1 (RIPK1) in primary CCA tissues was assayed by Immunohistochemical staining and their associations with clinicopathological characteristics and survival data were evaluated. The effects of TLR3 ligand, Poly(I:C) and Smac mimetic, an IAP antagonist on CCA cell death and invasion were determined by cell death detection methods and Transwell invasion assay, respectively. Both genetic and pharmacological inhibition of RIPK1, RIPK3 and MLKL and inhibitors targeting NF-κB and MAPK signaling were used to investigate the underlying mechanisms. Results TLR3 was significantly higher expressed in tumor than adjacent normal tissues. We demonstrated in a panel of CCA cell lines that TLR3 was frequently expressed in CCA cell lines, but was not detected in a nontumor cholangiocyte. Subsequent in vitro study demonstrated that Poly(I:C) specifically induced CCA cell death, but only when cIAPs were removed by Smac mimetic. Cell death was also switched from apoptosis to necroptosis when caspases were inhibited in CCA cells-expressing RIPK3. In addition, RIPK1 was required for Poly(I:C) and Smac mimetic-induced apoptosis and necroptosis. Of particular interest, high TLR3 or low RIPK1 status in CCA patients was associated with more invasiveness. In vitro invasion demonstrated that Poly(I:C)-induced invasion through NF-κB and MAPK signaling. Furthermore, the loss of RIPK1 enhanced Poly(I:C)-induced invasion and ERK activation in vitro. Smac mimetic also reversed Poly(I:C)-induced invasion, partly mediated by RIPK1. Finally, a subgroup of patients with high TLR3 and high RIPK1 had a trend toward longer disease-free survival (p = 0.078, 28.0 months and 10.9 months). Conclusion RIPK1 plays a pivotal role in TLR3 ligand, Poly(I:C)-induced cell death when cIAPs activity was inhibited and loss of RIPK1 enhanced Poly(I:C)-induced invasion which was partially reversed by Smac mimetic. Our results suggested that TLR3 ligand in combination with Smac mimetic could provide therapeutic benefits to the patients with CCA. Graphical abstract

scholarly journals Direct Costimulatory Effect of TLR3 Ligand Poly(I:C) on Human γδ T Lymphocytes

2006 ◽  
Vol 176 (3) ◽  
pp. 1348-1354 ◽  
Author(s):  
Daniela Wesch ◽  
Susann Beetz ◽  
Hans-Heinrich Oberg ◽  
Matthias Marget ◽  
Kirsten Krengel ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Poly I:C ◽  
Tlr3 Ligand Poly

scholarly journals A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses

2007 ◽  
Vol 204 (12) ◽  
pp. 2963-2976 ◽  
Author(s):  
Koichiro Takahashi ◽  
Takuma Shibata ◽  
Sachiko Akashi-Takamura ◽  
Takashi Kiyokawa ◽  
Yasutaka Wakabayashi ◽  
...  
Keyword(s):  
Cell Surface ◽  
Immune Responses ◽  
Poly I:C ◽  
Toll Like Receptor ◽  
T Helper ◽  
Surface Molecules ◽  
Adaptive Immune ◽  
And Function ◽  
Tlr3 Ligand Poly

Immune cells express multiple Toll-like receptors (TLRs) that are concomitantly activated by a variety of pathogen products. Although there is presumably a need to coordinate the expression and function of TLRs in individual cells, little is known about the mechanisms governing this process. We show that a protein associated with TLR4 (PRAT4A) is required for multiple TLR responses. PRAT4A resides in the endoplasmic reticulum, and PRAT4A knockdown inhibited trafficking of TLR1 and TLR4 to the cell surface and ligand-induced trafficking of TLR9 to lysosomes. Other cell-surface molecules were expressed normally on immunocytes from PRAT4A−/− mice. There was impaired cytokine production to TLR ligands, except to the TLR3 ligand poly(I:C), and to whole bacteria. Activation of antigen-specific T helper type 1 responses were also defective. Moreover, PRAT4A−/− bone marrow chimeric mice were resistant to lipopolysaccharide-induced sepsis. These results suggest that PRAT4A regulates the subcellular distribution and response of multiple TLRs and is required for both innate and adaptive immune responses.

scholarly journals Priming With Toll-Like Receptor 3 Agonist Poly(I:C) Enhances Content of Innate Immune Defense Proteins but Not MicroRNAs in Human Mesenchymal Stem Cell-Derived Extracellular Vesicles

2021 ◽  
Vol 9 ◽  
Author(s):  
Lisa M. Pierce ◽  
Wendy E. Kurata
Keyword(s):  
Innate Immunity ◽  
Extracellular Vesicles ◽  
Acute Phase ◽  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Immune Defense ◽  
Poly I:C ◽  
Toll Like Receptor ◽  
Bacterial Killing ◽  
Defense Proteins

Mesenchymal stem cells (MSCs) help fight infection by promoting direct bacterial killing or indirectly by modulating the acute phase response, thereby decreasing tissue injury. Recent evidence suggests that extracellular vesicles (EVs) released from MSCs retain antimicrobial characteristics that may be enhanced by pretreatment of parent MSCs with the toll-like receptor 3 (TLR3) agonist poly(I:C). Our aim was to determine whether poly(I:C) priming can modify EV content of miRNAs and/or proteins to gain insight into the molecular mechanisms of their enhanced antimicrobial function. Human bone marrow-derived MSCs were cultured with or without 1 μg/ml poly(I:C) for 1 h and then conditioned media was collected after 64 h of culture in EV-depleted media. Mass spectrometry and small RNA next-generation sequencing were performed to compare proteomic and miRNA profiles. Poly(I:C) priming resulted in 49 upregulated EV proteins, with 21 known to be important in host defense and innate immunity. In contrast, EV miRNA content was not significantly altered. Functional annotation clustering analysis revealed enrichment in biological processes and pathways including negative regulation of endopeptidase activity, acute phase, complement and coagulation cascades, innate immunity, immune response, and Staphylococcus aureus infection. Several antimicrobial peptides identified in EVs remained unaltered by poly(I:C) priming, including dermcidin, lactoferrin, lipocalin 1, lysozyme C, neutrophil defensin 1, S100A7 (psoriasin), S100A8/A9 (calprotectin), and histone H4. Although TLR3 activation of MSCs improves the proteomic profile of EVs, further investigation is needed to determine the relative importance of particular functional EV proteins and their activated signaling pathways following EV interaction with immune cells.

Key differences in TLR3/poly I:C signaling and cytokine induction by human primary cells: a phenomenon absent from murine cell systems

Blood ◽  
2007 ◽  
Vol 110 (9) ◽  
pp. 3245-3252 ◽  
Author(s):  
Anna M. Lundberg ◽  
Stefan K. Drexler ◽  
Claudia Monaco ◽  
Lynn M. Williams ◽  
Sandra M. Sacre ◽  
...  
Keyword(s):  
Viral Infections ◽  
Inflammatory Diseases ◽  
Synovial Fibroblasts ◽  
Cell Types ◽  
Poly I:C ◽  
Specific Response ◽  
Primary Cells ◽  
Human Primary Cells ◽  
Species Specific ◽  
Transformed Cell Lines

Abstract TLR3 recognizes double-stranded RNA, a product associated with viral infections. Many details of TLR3-induced mechanisms have emerged from gene-targeted mice or inhibition studies in transformed cell lines. However, the pathways activated in human immune cells or cells from disease tissue are less well understood. We have investigated TLR3-induced mechanisms of human primary cells of the innate immune system, including dendritic cells (DCs), macrophages (MØs), endothelial cells (ECs), and synovial fibroblasts isolated from rheumatoid arthritis joint tissue (RA-SFs). Here, we report that while these cells all express TLR3, they differ substantially in their response to TLR3 stimulation. The key antiviral response chemokine IP-10 was produced by all cell types, while DCs and MØs failed to produce the proinflammatory cytokines TNFα and IL-6. Unexpectedly, TNFα was found secreted by TLR3-stimulated RA-SF. Furthermore, TLR3 stimulation did not activate NFκB, MAPKs, or IRF-3 in DCs and MØs, but was able to do so in ECs and RA-SF. These findings were specific for human cells, thereby revealing a complexity not previously expected. This is the first report of such cell type– and species-specific response for any TLR stimulation and helps to explain important difficulties in correlating murine models of inflammatory diseases and human inflammation.

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