Cytosolic d ‐type CpG‐oligonucleotides induce a type I interferon response by activating the cGAS‐STING signaling pathway
Autor: | Dennis M. Klinman, Christian Bode, Jens M. Poth, Folkert Steinhagen, Eicke Latz, Mario Fox, Susanne Schulz |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
THP-1 Cells Immunology Biology Monocytes 03 medical and health sciences Cytosol 0302 clinical medicine Interferon medicine Humans Immunology and Allergy Phosphorylation Cells Cultured Macrophages Membrane Proteins TLR9 Signal transducing adaptor protein hemic and immune systems respiratory system Toll-Like Receptor 9 Cell biology HEK293 Cells 030104 developmental biology Oligodeoxyribonucleotides Stimulator of interferon genes Interferon Type I Interferon Regulatory Factor-3 Nucleotides Cyclic Signal transduction IRF3 Signal Transduction 030215 immunology Interferon regulatory factors medicine.drug |
Zdroj: | European Journal of Immunology. 51:1686-1697 |
ISSN: | 1521-4141 0014-2980 |
Popis: | Cytosolic DNA receptor cyclic GMP-AMP (cGAMP) synthase (cGAS) has been shown to be critically involved in the detection of cytosolic, self- and non-self-DNA, initiating a type I Interferon (IFN) response through the adaptor protein Stimulator of Interferon Genes (STING) and interferon regulatory factor 3 (IRF3). Current studies propose that canonical binding of dsDNA by cGAS depends on DNA length, but not base sequence. In contrast, activation of Toll-like receptor 9 (TLR9) is sequence-dependent. It requires unmethylated CpG dinucleotides in microbial DNA, which is mimicked by synthetic oligodeoxynucleotides (ODN). Here, we provide evidence that D-type ODN (D-ODN), but not K-type ODN (K-ODN), bind to human cGAS and activate downstream signaling. Transfection of D-ODN into a TLR9-deficient, human monocytic cell line (THP-1) induced phosphorylation of IRF3 and secretion of IFN. This response was absent in cells with CRISPR/Cas9-mediated cGAS- or STING-deficiency. Utilizing a protein pulldown approach, we further demonstrate direct binding of D-ODN to cGAS. Induction of a type I IFN response by D-ODN was confirmed in human primary monocytes and monocyte-derived macrophages. These results are relevant to our understanding of self-non-self-discrimination by cGAS and to the pharmacologic effects of ODN, which currently are investigated in clinical studies. This article is protected by copyright. All rights reserved. |
Databáze: | OpenAIRE |
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