TLR9 transcriptional regulation in response to double-stranded DNA viruses

• Published in: The Journal of immunology (1950) 2014-10, Vol.193 (7), p.3398-3408
• Main Authors: Zannetti, Claudia, Parroche, Peggy, Panaye, Marine, Roblot, Guillaume, Gruffat, Henri, Manet, Evelyne, Debaud, Anne Laure, Plumas, Joel, Vey, Nelly, Caux, Christophe, Bendriss-Vermare, Nathalie, Hasan, Uzma Ayesha
• Format: Article
• Language: English
• Subjects: Animals; Dendritic Cells - immunology; Dendritic Cells - pathology; DNA Virus Infections - genetics; DNA Virus Infections - immunology; DNA Virus Infections - pathology; DNA Viruses - immunology; Epithelial Cells - immunology; Epithelial Cells - pathology; Female; Gene Knockdown Techniques; HEK293 Cells; Histone Deacetylases - genetics; Histone Deacetylases - immunology; Humans; Male; Mice; NIH 3T3 Cells; Plasma Cells - immunology; Plasma Cells - pathology; Promoter Regions, Genetic - immunology; Toll-Like Receptor 9 - genetics; Toll-Like Receptor 9 - immunology; Transcription Factor RelA - genetics; Transcription Factor RelA - immunology; Transcription, Genetic - genetics; Transcription, Genetic - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1400249

The stimulation of TLRs by pathogen-derived molecules leads to the production of proinflammatory cytokines. Because uncontrolled inflammation can be life threatening, TLR regulation is important; however, few studies have identified the signaling pathways that contribute to the modulation of TLR expression. In this study, we examined the relationship between activation and the transcriptional regulation of TLR9. We demonstrate that infection of primary human epithelial cells, B cells, and plasmacytoid dendritic cells with dsDNA viruses induces a regulatory temporary negative-feedback loop that blocks TLR9 transcription and function. TLR9 transcriptional downregulation was dependent on TLR9 signaling and was not induced by TLR5 or other NF-κB activators, such as TNF-α. Engagement of the TLR9 receptor induced the recruitment of a suppressive complex, consisting of NF-κBp65 and HDAC3, to an NF-κB cis element on the TLR9 promoter. Knockdown of HDAC3 blocked the transient suppression in which TLR9 function was restored. These results provide a framework for understanding the complex pathways involved in transcriptional regulation of TLR9, immune induction, and inflammation against viruses.