scholarly journals RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA

2013 ◽  
Vol 210 (11) ◽  
pp. 2447-2463 ◽  
Author(s):  
Cherilyn M. Sirois ◽  
Tengchuan Jin ◽  
Allison L. Miller ◽  
Damien Bertheloot ◽  
Hirotaka Nakamura ◽  
...  
Keyword(s):  
Nucleic Acids ◽  
Inflammatory Responses ◽  
Immune Recognition ◽  
Dna Uptake ◽  
Rna Molecules ◽  
Receptor Complexes ◽  
Dna And Rna ◽  
Signaling Receptors ◽  
Mammalian Immune System

Recognition of DNA and RNA molecules derived from pathogens or self-antigen is one way the mammalian immune system senses infection and tissue damage. Activation of immune signaling receptors by nucleic acids is controlled by limiting the access of DNA and RNA to intracellular receptors, but the mechanisms by which endosome-resident receptors encounter nucleic acids from the extracellular space are largely undefined. In this study, we show that the receptor for advanced glycation end-products (RAGE) promoted DNA uptake into endosomes and lowered the immune recognition threshold for the activation of Toll-like receptor 9, the principal DNA-recognizing transmembrane signaling receptor. Structural analysis of RAGE–DNA complexes indicated that DNA interacted with dimers of the outermost RAGE extracellular domains, and could induce formation of higher-order receptor complexes. Furthermore, mice deficient in RAGE were unable to mount a typical inflammatory response to DNA in the lung, indicating that RAGE is important for the detection of nucleic acids in vivo.

Methylation of Guanine in vivo by the Organophosphorus Insecticide Methamidophos*

1987 ◽  
Vol 42 (1-2) ◽  
pp. 17-20 ◽  
Author(s):  
Salah M . A . D . Zayed ◽  
Fathya M. Mahdi
Keyword(s):  
Nucleic Acids ◽  
Mouse Liver ◽  
Organophosphorus Insecticide ◽  
Appreciable Amount ◽  
Dna And Rna ◽  
Applied Dose

Abstract The methylating capability of methamidophos, assayed by the formation of [7-14C]methylguanine in mouse liver, was investigated using a 14C-insecticide labelled at the O -CH3 group. Following i.p. administration of the toxicant, [7-14C]methylguanine could be isolated from liver nucleic acids of treated mice. The amount of 14C-label reached its maximum 6 h follow ing administration of the insecticide. At maximum 14C-labelling, the amount of 7-methylguanine calculated as fraction of applied dose, was 20-22 × 10-4 and 98 -104 x-4, for DNA and RNA , respectively. The results obtained indicate also, that an appreciable amount of I4C-activity is incorporated via the C-1 pool.

THE SYNTHESIS OF DNA AND RNA IN NORMAL HUMAN ENDOMETRIUM IN SHORT-TERM INCUBATION IN VITRO AND ITS RESPONSE TO OESTRADIOL AND PROGESTERONE

1970 ◽  
Vol 48 (1) ◽  
pp. 17-28 ◽  
Author(s):  
S. NORDQVIST
Keyword(s):  
Nucleic Acids ◽  
Dna Synthesis ◽  
Acid Synthesis ◽  
Short Term ◽  
Normal Endometrium ◽  
Dna And Rna ◽  
Progesterone Synthesis ◽  
Normal Human

SUMMARY A method is described for short-term incubations in vitro of normal endometrium for the study of nucleic acid synthesis. Tissue suspensions of specimens obtained at curettage were incubated with and without hormones in a medium consisting of Parker's 199 medium and 20% adult human serum; [3H]thymidine and [14C]uridine were added. The isotope uptake into the nucleic acids was determined and related to the total amount of DNA in each sample. Marked variation in DNA synthesis was noted in endometria obtained at different phases of the menstrual cycle. RNA synthesis varied less. After the addition of progesterone, synthesis of both nucleic acids was reduced. The magnitude of this response varied in different endometria. Thus DNA synthesis in endometria already under strong progesterone influence in vivo (midsecretory phase) was least affected when progesterone was added in vitro.

scholarly journals A world beyond double-helical nucleic acids: the structural diversity of tetra-stranded G-quadruplexes

ChemTexts ◽  
2021 ◽  
Vol 7 (4) ◽  
Author(s):  
Klaus Weisz
Keyword(s):  
Hydrogen Bond ◽  
Nucleic Acids ◽  
Genetic Information ◽  
Structural Diversity ◽  
Base Pairing ◽  
Rna Sequences ◽  
Dna And Rna ◽  
Regulatory Functions ◽  
Insight Into

AbstractNucleic acids can adopt various secondary structures including double-, triple-, and tetra-stranded helices that differ by the specific hydrogen bond mediated pairing pattern between their nucleobase constituents. Whereas double-helical DNA relies on Watson–Crick base pairing to play a prominent role in storing genetic information, G-quadruplexes are tetra-stranded structures that are formed by the association of guanine bases from G-rich DNA and RNA sequences. During the last few decades, G-quadruplexes have attracted considerable interest after the realization that they form and exert regulatory functions in vivo. In addition, quadruplex architectures have also been recognized as versatile and powerful tools in a growing number of technological applications. To appreciate the astonishing structural diversity of these tetra-stranded structures and to give some insight into basic interactions that govern their folding, this article gives an overview of quadruplex structures and rules associated with the formation of different topologies. A brief discussion will also focus on nonconventional quadruplexes as well as on general principles when targeting quadruplexes with ligands. Graphic abstract

scholarly journals The immunorecognition, subcellular compartmentalization, and physicochemical properties of nucleic acid nanoparticles can be controlled by composition modification

2020 ◽  
Vol 48 (20) ◽  
pp. 11785-11798
Author(s):  
Morgan Brittany Johnson ◽  
Justin R Halman ◽  
Daniel K Miller ◽  
Joseph S Cooper ◽  
Emil F Khisamutdinov ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Immune Responses ◽  
Nucleic Acids ◽  
Targeted Delivery ◽  
Inflammatory Responses ◽  
Diagnostic Tools ◽  
Immune Recognition ◽  
Composition Modification ◽  
Target Molecules ◽  
Subcellular Compartmentalization

Abstract Nucleic acid nanoparticles (NANPs) have become powerful new platforms as therapeutic and diagnostic tools due to the innate biological ability of nucleic acids to identify target molecules or silence genes involved in disease pathways. However, the clinical application of NANPs has been limited by factors such as chemical instability, inefficient intracellular delivery, and the triggering of detrimental inflammatory responses following innate immune recognition of nucleic acids. Here, we have studied the effects of altering the chemical composition of a circumscribed panel of NANPs that share the same connectivity, shape, size, charge and sequences. We show that replacing RNA strands with either DNA or chemical analogs increases the enzymatic and thermodynamic stability of NANPs. Furthermore, we have found that such composition changes affect delivery efficiency and determine subcellular localization, effects that could permit the targeted delivery of NANP-based therapeutics and diagnostics. Importantly, we have determined that altering NANP composition can dictate the degree and mechanisms by which cell immune responses are initiated. While RNA NANPs trigger both TLR7 and RIG-I mediated cytokine and interferon production, DNA NANPs stimulate minimal immune activation. Importantly, incorporation of 2′F modifications abrogates RNA NANP activation of TLR7 but permits RIG-I dependent immune responses. Furthermore, 2′F modifications of DNA NANPs significantly enhances RIG-I mediated production of both proinflammatory cytokines and interferons. Collectively this indicates that off-target effects may be reduced and/or desirable immune responses evoked based upon NANPs modifications. Together, our studies show that NANP composition provides a simple way of controlling the immunostimulatory potential, and physicochemical and delivery characteristics, of such platforms.

scholarly journals Pelagic-Benthic Coupling of Nucleic Acids in an Abyssal Location of the Northeastern Atlantic Ocean

1999 ◽  
Vol 65 (10) ◽  
pp. 4451-4457 ◽  
Author(s):  
A. Dell’Anno ◽  
M. Fabiano ◽  
M. L. Mei ◽  
R. Danovaro
Keyword(s):  
Nucleic Acid ◽  
Atlantic Ocean ◽  
Nucleic Acids ◽  
Sediment Traps ◽  
Temporal Changes ◽  
Rna Molecules ◽  
Dna And Rna ◽  
Northeastern Atlantic Ocean ◽  
Benthic Coupling ◽  
Northeastern Atlantic

ABSTRACT Spatial and temporal changes in sedimentary nucleic acid concentrations in an abyssal locality of the northeastern Atlantic Ocean were investigated in relation to fluxes of nucleic acids produced in the photic layer. Sediment trap material, collected between 1996 and 1998 at depths of 1,000, 3,000, and 4,700 m, and sediment samples were analyzed for DNA and RNA content. Nucleic acid concentrations in the sediments were very high and displayed significant temporal changes, whereas mesoscale variability was low. DNA and RNA concentrations generally displayed opposite temporal patterns, which are likely to be dependent on the nature and characteristics of DNA and RNA molecules. Nucleic acid fluxes were high and displayed clear seasonal changes apparently coupled with seasonal pulses of primary production. However, while median values of DNA fluxes were relatively similar in all sediment traps, median values of RNA fluxes almost doubled from the 1,000- to the 4,700-m depth, suggesting differences in the metabolic activity of microbes associated with sinking particles. Significant relationships between DNA concentrations in the sediments and DNA fluxes and between RNA concentrations and RNA fluxes, indicating the presence of a clear pelagic-benthic coupling of particulate nucleic acids, were observed. The benthic system investigated was not steady state since we estimated that, from September 1996 to October 1998, nucleic acid concentration in the sediments decreased by about 165 mg of DNA m−2. Vertical profiles revealed a significant decrease in DNA concentration with depth in the sediments, reaching an asymptotic value of about 5 μg g−1. This DNA fraction constitutes a pool of potentially refractory DNA (accounting for 16 to 40% of the total DNA pool) that might be buried in the sediments.

scholarly journals Plasmacytoid dendritic cells sense skin injury and promote wound healing through type I interferons

2010 ◽  
Vol 207 (13) ◽  
pp. 2921-2930 ◽  
Author(s):  
Josh Gregorio ◽  
Stephan Meller ◽  
Curdin Conrad ◽  
Anna Di Nardo ◽  
Bernhard Homey ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Nucleic Acids ◽  
Wound Repair ◽  
Inflammatory Responses ◽  
Plasmacytoid Dendritic Cells ◽  
Type I Interferons ◽  
Type I ◽  
Immune Recognition ◽  
Skin Wounds ◽  
Common Skin

Plasmacytoid dendritic cells (pDCs) are specialized type I interferon (IFN-α/β)–producing cells that express intracellular toll-like receptor (TLR) 7 and TLR9 and recognize viral nucleic acids in the context of infections. We show that pDCs also have the ability to sense host-derived nucleic acids released in common skin wounds. pDCs were found to rapidly infiltrate both murine and human skin wounds and to transiently produce type I IFNs via TLR7- and TLR9-dependent recognition of nucleic acids. This process was critical for the induction of early inflammatory responses and reepithelization of injured skin. Cathelicidin peptides, which facilitate immune recognition of released nucleic acids by promoting their access to intracellular TLR compartments, were rapidly induced in skin wounds and were sufficient but not necessary to stimulate pDC activation and type I IFN production. These data uncover a new role of pDCs in sensing tissue damage and promoting wound repair at skin surfaces.

scholarly journals Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses

2021 ◽  
Vol 13 (580) ◽  
pp. eabd3438
Author(s):  
Ying Kai Chan ◽  
Sean K. Wang ◽  
Colin J. Chu ◽  
David A. Copland ◽  
Alexander J. Letizia ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Nucleic Acids ◽  
Viral Vectors ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Therapeutic Window ◽  
Therapeutic Modalities ◽  
Dna Oligonucleotides

Nucleic acids are used in many therapeutic modalities, including gene therapy, but their ability to trigger host immune responses in vivo can lead to decreased safety and efficacy. In the case of adeno-associated viral (AAV) vectors, studies have shown that the genome of the vector activates Toll-like receptor 9 (TLR9), a pattern recognition receptor that senses foreign DNA. Here, we engineered AAV vectors to be intrinsically less immunogenic by incorporating short DNA oligonucleotides that antagonize TLR9 activation directly into the vector genome. The engineered vectors elicited markedly reduced innate immune and T cell responses and enhanced gene expression in clinically relevant mouse and pig models across different tissues, including liver, muscle, and retina. Subretinal administration of higher-dose AAV in pigs resulted in photoreceptor pathology with microglia and T cell infiltration. These adverse findings were avoided in the contralateral eyes of the same animals that were injected with the engineered vectors. However, intravitreal injection of higher-dose AAV in macaques, a more immunogenic route of administration, showed that the engineered vector delayed but did not prevent clinical uveitis, suggesting that other immune factors in addition to TLR9 may contribute to intraocular inflammation in this model. Our results demonstrate that linking specific immunomodulatory noncoding sequences to much longer therapeutic nucleic acids can “cloak” the vector from inducing unwanted immune responses in multiple, but not all, models. This “coupled immunomodulation” strategy may widen the therapeutic window for AAV therapies as well as other DNA-based gene transfer methods.

Anti-β2 Glycoprotein I Antibodies Cause Inflammation and Recruit Dendritic Cells in Platelet Clearance

2001 ◽  
Vol 86 (11) ◽  
pp. 1257-1263 ◽  
Author(s):  
Attilio Bondanza ◽  
Angelo Manfredi ◽  
Valérie Zimmermann ◽  
Matteo Iannacone ◽  
Angela Tincani ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Inflammatory Responses ◽  
Glycoprotein I ◽  
Activated Platelets ◽  
Tnf Α ◽  
Per Se ◽  
Antigen Presenting ◽  
Antiinflammatory Cytokine

SummaryScavenger phagocytes are mostly responsible for the in vivo clearance of activated or senescent platelets. In contrast to other particulate substrates, the phagocytosis of platelets does not incite pro-inflammatory responses in vivo. This study assessed the contribution of macrophages and dendritic cells (DCs) to the clearance of activated platelets. Furthermore, we verified whether antibodies against the β2 Glycoprotein I (β2GPI), which bind to activated platelets, influence the phenomenon. DCs did not per se internalise activated platelets. In contrast, macrophages efficiently phagocytosed platelets. In agreement with the uneventful nature of the clearance of platelets in vivo, phagocytosing macrophages did not release IL-1β, TNF-α or IL-10. β2GPI bound to activated platelets and was required for their recognition by anti-ββ2GPI antibodies. DCs internalised platelets opsonised by anti-ββ2GPI antibodies. The phagocytosis of opsonised platelets determined the release of TNF-α and IL-1β by DCs and macrophages. Phagocytosing macrophages, but not DCs, secreted the antiinflammatory cytokine IL-1β0. We conclude that anti-ββ2GPI antibodies cause inflammation during platelet clearance and shuttle platelet antigens to antigen presenting DCs.

Sign in / Sign up

Export Citation Format

Share Document