Triggering of the cGAS-STING Pathway in Human Plasmacytoid Dendritic Cells Inhibits TLR9-Mediated IFN Production
Open accessAbstract
Plasmacytoid dendritic cells (pDCs) are potent producers of type I and type III IFNs and play a major role in antiviral immunity and autoimmune disorders. The innate sensing of nucleic acids remains the major initiating factor for IFN production by pDCs. TLR-mediated sensing of nucleic acids via endosomal pathways has been studied and documented in detail, whereas the sensing of DNA in cytosolic compartment in human pDCs remains relatively unexplored. We now demonstrate the existence and functionality of the components of cytosolic DNA-sensing pathway comprising cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of IFN gene (STING) in human pDCs. cGAS was initially located in the cytosolic compartment of pDCs and time-dependently colocalized with non-CpG double-stranded immunostimulatory DNA (ISD). Following the colocalization of ISD with cGAS, the downstream pathway was triggered as STING disassociated from its location at the endoplasmic reticulum. Upon direct stimulation of pDCs by STING agonist 2′3′ cGAMP or dsDNA, pDC-s produced type I, and type III IFN. Moreover, we documented that cGAS–STING–mediated IFN production is mediated by nuclear translocation of IRF3 whereas TLR9-mediated activation occurs through IRF7. Our data also indicate that pDC prestimulation of cGAS–STING dampened the TLR9-mediated IFN production. Furthermore, triggering of cGAS–STING induced expression of SOCS1 and SOCS3 in pDCs, indicating a possible autoinhibitory loop that impedes IFN production by pDCs. Thus, our study indicates that the cGAS–STING pathway exists in parallel to the TLR9-mediated DNA recognition in human pDCs with cross-talk between these two pathways.
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pDCs express high levels of TLR7 and TLR9 in their endosomes and the cytoplasmic DNA sensor cGAS, enabling detection of viral DNA and single-stranded RNA genomes and production of high amounts of IFN-I upon TLR or cGAS activation.
“pDCs express high levels of TLR7 and TLR9 in their endosomes as well as the cytoplasmic DNA sensor cGAS and are thus well equipped to detect viral DNA and single-stranded RNA genomes and produce high amounts of IFN-I upon TLR or cGAS activation.46,47,48,49”
From TLR9-independent CD8+ T cell responses in hepatic AAV gene transfer through IL-1R1-MyD88 signaling (2024) · cites this paper as [48]
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- Authors
- Deb, P., Dai, J., Singh, S., Kalyoussef, E., & Fitzgerald-Bocarsly, P.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Rutgers New Jersey Medical School (US)
- Corresponding author
- Deb, Pratik
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-07-01
- Volume
- 205
- Issue
- 1
- Pages
- 223-236
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC7460725
- OpenAlex
- W3030603206
- Cited by
- 72
- References
- 65
- Citations by year
- 2026: 15 · 2025: 7 · 2024: 15 · 2023: 12 · 2022: 13 · 2021: 7 · 2020: 3
- FWCI
- 3.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI026806, R01AI106125)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- cGAS-STING pathway, plasmacytoid dendritic cells, TLR9, interferon production, cytosolic DNA sensing, immunostimulatory DNA, IRF3 nuclear translocation, IRF7, SOCS1, SOCS3, autoinhibition, innate immunity, antiviral immunity, pathway crosstalk
- MeSH terms
- Suppressor of Cytokine Signaling 1 Protein, Suppressor of Cytokine Signaling 3 Protein, THP-1 Cells, STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Dendritic Cells, DNA, Endoplasmic Reticulum, Humans, Interferons, Membrane Proteins, Nucleotides, Cyclic, Nucleotidyltransferases, Signal Transduction, Interferon Regulatory Factor-3, Interferon Regulatory Factor-7, Toll-Like Receptor 9, Primary Cell Culture
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