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
Rok vydání: 2021
Předmět:
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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