scholarly journals Interplay of Cyclic GMP-AMP Synthase/Stimulator of IFN Genes and Toll-Like Receptor Nucleic Acid Sensing Pathways in Autoinflammation and Abnormal Bone Formation due to DNaseII-Deficiency

2020 ◽  
Vol 33 (3) ◽  
pp. 246-249
Author(s):  
Ann Marshak-Rothstein ◽  
Catherine A. Manning ◽  
Rebecca Baum ◽  
Sudesh Pawaria ◽  
Ellen M. Gravallese
Keyword(s):  
Nucleic Acid ◽  
Bone Formation ◽  
Cyclic Gmp ◽  
Toll Like Receptor

scholarly journals Nucleic acid agonists for Toll-like receptor 7 are defined by the presence of uridine ribonucleotides

2006 ◽  
Vol 36 (12) ◽  
pp. 3256-3267 ◽  
Author(s):  
Sandra S. Diebold ◽  
Catherine Massacrier ◽  
Shizuo Akira ◽  
Carine Paturel ◽  
Yannis Morel ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Toll Like Receptor

scholarly journals The cGAS/STING–TBK1–IRF Regulatory Axis Orchestrates a Primitive Interferon-Like Antiviral Mechanism in Oyster

2021 ◽  
Vol 12 ◽  
Author(s):  
Xue Qiao ◽  
Yanan Zong ◽  
Zhaoqun Liu ◽  
Zhaojun Wu ◽  
Yuanmei Li ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Mrna Expression ◽  
Cyclic Gmp ◽  
Crassostrea Gigas ◽  
Nuclear Translocation ◽  
Signal Pathway ◽  
Poly I:C ◽  
High Level ◽  
Antiviral Mechanism ◽  
Interferon Gene

Interferon (IFN) system is considered as the first defense line against viral infection, and it has been extensively studied in vertebrates from fish to mammals. In invertebrates, Vagos from arthropod and IFN-like protein (CgIFNLP) from Crassostrea gigas appeared to function as IFN-like antiviral cytokines. In the present study, the CgIFNLP protein in hemocytes was observed to increase after Poly (I:C) stimulation. After CgIFNLP was knocked down by RNAi, the mRNA expression of IFN-stimulated genes (CgISGs) was significantly inhibited. Both cyclic GMP-AMP synthase (CgcGAS) and stimulator of interferon gene (CgSTING) identified from oyster were able to recognize the double-stranded nucleic acid [Poly (I:C) and dsDNA] and expressed at high level after Poly (I:C) stimulation. The expression of CgIFNLP and interferon regulatory factors (CgIRF1/8) and the nuclear translocation of CgIRF8 were all suppressed in CgcGAS-RNAi or CgSTING-RNAi oysters after Poly (I:C) stimulation. The expression level of CgSTING and TANK binding kinase1 (CgTBK1) did not decrease in CgcGAS-RNAi oysters. After CgSTING was knocked down, the high expression of CgTBK1 induced by Poly (I:C) was prevented significantly. These results indicated that there was a primitive IFN-like antiviral mechanism dependent on the cGAS/STING–TBK1–IRFs regulatory axis in mollusks, which was different from the classic cGAS–STING–TBK1 signal pathway in mammals.

scholarly journals Human macrophages utilize a wide range of pathogen recognition receptors to recognize Legionella pneumophila, including Toll-Like Receptor 4 engaging Legionella lipopolysaccharide and the Toll-like Receptor 3 nucleic-acid sensor

2021 ◽  
Vol 17 (7) ◽  
pp. e1009781
Author(s):  
Lubov S. Grigoryeva ◽  
Nicholas P. Cianciotto
Keyword(s):  
Nucleic Acid ◽  
Legionella Pneumophila ◽  
Critical Role ◽  
U937 Cells ◽  
Toll Like Receptor ◽  
Lectin Receptors ◽  
Macrophage Response ◽  
Human Macrophages ◽  
Wide Range ◽  
Pathogen Recognition Receptors

Cytokines made by macrophages play a critical role in determining the course of Legionella pneumophila infection. Prior murine-based modeling indicated that this cytokine response is initiated upon recognition of L. pneumophila by a subset of Toll-like receptors, namely TLR2, TLR5, and TLR9. Through the use of shRNA/siRNA knockdowns and subsequently CRISPR/Cas9 knockouts (KO), we determined that TRIF, an adaptor downstream of endosomal TLR3 and TLR4, is required for full cytokine secretion by human primary and cell-line macrophages. By characterizing a further set of TLR KO’s in human U937 cells, we discerned that, contrary to the viewpoint garnered from murine-based studies, TLR3 and TLR4 (along with TLR2 and TLR5) are in fact vital to the macrophage response in the early stages of L. pneumophila infection. This conclusion was bolstered by showing that i) chemical inhibitors of TLR3 and TLR4 dampen the cytokine output of primary human macrophages and ii) transfection of TLR3 and TLR4 into HEK cells conferred an ability to sense L. pneumophila. TLR3- and TLR4-dependent cytokines promoted migration of human HL-60 neutrophils across an epithelial layer, pointing to the biological importance for the newfound signaling pathway. The response of U937 cells to L. pneumophila LPS was dependent upon TLR4, a further contradiction to murine-based studies, which had concluded that TLR2 is the receptor for Legionella LPS. Given the role of TLR3 in sensing nucleic acid (i.e., dsRNA), we utilized newly-made KO U937 cells to document that DNA-sensing by cGAS-STING and DNA-PK are also needed for the response of human macrophages to L. pneumophila. Given the lack of attention given them in the bacterial field, C-type lectin receptors were similarly examined; but, they were not required. Overall, this study arguably represents the most extensive, single-characterization of Legionella-recognition receptors within human macrophages.

scholarly journals Toll-Like Receptor-Mediated Recognition of Nucleic Acid Nanoparticles (NANPs) in Human Primary Blood Cells

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1094 ◽  
Author(s):  
Enping Hong ◽  
Justin Halman ◽  
Ankit Shah ◽  
Edward Cedrone ◽  
Nguyen Truong ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Rational Design ◽  
Size Composition ◽  
Immune Recognition ◽  
Toll Like Receptor ◽  
Structure Activity ◽  
Infusion Reactions ◽  
Major Route ◽  
Comprehensive Study

Infusion reactions (IRs) create a translational hurdle for many novel therapeutics, including those utilizing nanotechnology. Nucleic acid nanoparticles (NANPs) are a novel class of therapeutics prepared by rational design of relatively short oligonucleotides to self-assemble into various programmable geometric shapes. While cytokine storm, a common type of IR, has halted clinical development of several therapeutic oligonucleotides, NANP technologies hold tremendous potential to bring these reactions under control by tuning the particle’s physicochemical properties to the desired type and magnitude of the immune response. Recently, we reported the very first comprehensive study of the structure–activity relationship between NANPs’ shape, size, composition, and their immunorecognition in human cells, and identified the phagolysosomal pathway as the major route for the NANPs’ uptake and subsequent immunostimulation. Here, we explore the molecular mechanism of NANPs’ recognition by primary immune cells, and particularly the contributing role of the Toll-like receptors. Our current study expands the understanding of the immune recognition of engineered nucleic acid-based therapeutics and contributes to the improvement of the nanomedicine safety profile.

Cyclic GMP-dependent protein kinase II is necessary for macrophage M1 polarization and phagocytosis via toll-like receptor 2

2014 ◽  
Vol 93 (5) ◽  
pp. 523-533 ◽  
Author(s):  
Wei-Ting Liao ◽  
Huey-Ling You ◽  
Changgui Li ◽  
Jan-Gowth Chang ◽  
Shun-Jen Chang ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cyclic Gmp ◽  
Toll Like Receptor ◽  
Dependent Protein Kinase ◽  
M1 Polarization ◽  
Protein Kinase Ii ◽  
Dependent Protein ◽  
Toll Like Receptor 2

scholarly journals Nucleic acid recognition by Toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase

2011 ◽  
Vol 208 (4) ◽  
pp. 643-651 ◽  
Author(s):  
Sarah E. Ewald ◽  
Alex Engel ◽  
Jiyoun Lee ◽  
Miqi Wang ◽  
Matthew Bogyo ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Cell Types ◽  
Proteolytic Processing ◽  
Toll Like Receptor ◽  
The Core ◽  
Regulatory Strategy ◽  
Mouse Macrophages ◽  
Initial Cleavage ◽  
Analogous Manner ◽  
Multistep Process

Toll-like receptor (TLR) 9 requires proteolytic processing in the endolysosome to initiate signaling in response to DNA. However, recent studies conflict as to which proteases are required for receptor cleavage. We show that TLR9 proteolysis is a multistep process. The first step removes the majority of the ectodomain and can be performed by asparagine endopeptidase (AEP) or cathepsin family members. This initial cleavage event is followed by a trimming event that is solely cathepsin mediated and required for optimal receptor signaling. This dual requirement for AEP and cathepsins is observed in all cell types that we have analyzed, including mouse macrophages and dendritic cells. In addition, we show that TLR7 and TLR3 are processed in an analogous manner. These results define the core proteolytic steps required for TLR9 function and suggest that receptor proteolysis may represent a general regulatory strategy for all TLRs involved in nucleic acid recognition.

scholarly journals Toll-like receptor 2 promiscuity is responsible for the immunostimulatory activity of nucleic acid nanocarriers

2017 ◽  
Vol 247 ◽  
pp. 182-193 ◽  
Author(s):  
Malvina Pizzuto ◽  
Monique Gangloff ◽  
Daniel Scherman ◽  
Nicholas J. Gay ◽  
Virginie Escriou ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Toll Like Receptor ◽  
Immunostimulatory Activity ◽  
Toll Like Receptor 2

scholarly journals B cell receptor and Toll-like receptor signaling coordinate to control distinct B-1 responses to both self and the microbiota

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Lieselotte SM Kreuk ◽  
Meghan A Koch ◽  
Leianna C Slayden ◽  
Nicholas A Lind ◽  
Sophia Chu ◽  
...  
Keyword(s):  
Steady State ◽  
Nucleic Acid ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Tissue Homeostasis ◽  
Toll Like Receptor ◽  
Reporter Mouse ◽  
Bcr Signaling ◽  
Natural Igm ◽  
Antibody Secretion

B-1a cells play an important role in mediating tissue homeostasis and protecting against infections. They are the main producers of ‘natural’ IgM, spontaneously secreted serum antibodies predominately reactive to self antigens, like phosphatidylcholine (PtC), or antigens expressed by the intestinal microbiota. The mechanisms that regulate the B-1a immunoglobulin (Ig) repertoire and their antibody secretion remain poorly understood. Here, we use a novel reporter mouse to demonstrate that production of self- and microbiota-reactive antibodies is linked to BCR signaling in B-1a cells. Moreover, we show that Toll-like receptors (TLRs) are critical for shaping the Ig repertoire of B-1a cells as well as regulating their antibody production. Strikingly, we find that both the colonization of a microbiota as well as microbial-sensing TLRs are required for anti-microbiota B-1a responses, whereas nucleic-acid sensing TLRs are required for anti-PtC responses, demonstrating that linked activation of BCR and TLRs controls steady state B-1a responses to both self and microbiota-derived antigens.

scholarly journals Unc93b1 recruits Syntenin-1 to dampen TLR7 signaling and prevent autoimmunity

2018 ◽  
Author(s):  
Olivia Majer ◽  
Bo Liu ◽  
Nevan Krogan ◽  
Gregory M. Barton
Keyword(s):  
Endoplasmic Reticulum ◽  
Nucleic Acid ◽  
Autoimmune Diseases ◽  
Negative Regulation ◽  
Innate Immune ◽  
Regulatory Function ◽  
Toll Like Receptor ◽  
Activation Threshold ◽  
Dynamic Regulation ◽  
Tlr9 Signaling

AbstractRecognition of nucleic acids enables detection of diverse pathogens by a limited number of innate immune receptors but also exposes the host to potential autoimmunity. At least two members of the Toll-like receptor (TLR) family, TLR7 and TLR9, can recognize self RNA or DNA, respectively. Despite the structural and functional similarities between these receptors, their contribution to autoimmune diseases such as SLE can be quite different. However, mechanisms of negative regulation that differentiate between TLR7 and TLR9 have not been described. Here we report a new function for the TLR trafficking chaperone Unc93b1 that specifically limits TLR7 signaling and prevents TLR7-dependent autoimmunity. Unc93b1 is known to traffic TLRs from the endoplasmic reticulum to endosomes, but this new regulatory function does not affect TLR7 localization. Instead, Unc93b1 recruits Syntenin-1, which inhibits TLR7, but not TLR9, signaling. Syntenin-1 binding requires phosphorylation of two serine residues on Unc93b1, providing a mechanism for dynamic regulation of the activation threshold of TLR7. Disruption of the Unc93b1/Syntenin-1 interaction in mice results in TLR7-dependent autoimmunity. Thus, Unc93b1 not only enables proper trafficking of nucleic acid sensing TLRs but also sets the activation threshold of these potentially self-reactive receptors.

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