S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 5; pp. 1351 - 1356
• Main Authors: Teijaro, John R., Studer, Sean, Leaf, Nora, Kiosses, William B., Nguyen, Nhan, Matsuki, Kosuke, Negishi, Hideo, Taniguchi, Tadatsugu, Oldstone, Michael B. A., Rosen, Hugh
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02.02.2016; National Acad Sciences
• Subjects: Animals; Biological Sciences; Dendritic Cells - metabolism; Interferon-alpha - metabolism; Mice; Mice, Knockout; Proteolysis; Receptor, Interferon alpha-beta - genetics; Receptor, Interferon alpha-beta - metabolism; Receptors, Lysosphingolipid - physiology; S1PR1; plasmacytoid dendritic cell; interferon-α; sphingosine 1-phosphate; IFNAR1
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1525356113

Blunting immunopathology without abolishing host defense is the foundation for safe and effective modulation of infectious and autoimmune diseases. Sphingosine 1-phosphate receptor 1 (S1PR1) agonists are effective in treating infectious and multiple autoimmune pathologies; however, mechanisms underlying their clinical efficacy are yet to be fully elucidated. Here, we uncover an unexpected mechanism of convergence between S1PR1 and interferon alpha receptor 1 (IFNAR1) signaling pathways. Activation of S1PR1 signaling by pharmacological tools or endogenous ligand sphingosine-1 phosphate (S1P) inhibits type 1 IFN responses that exacerbate numerous pathogenic conditions. Mechanistically, S1PR1 selectively suppresses the type I IFN autoamplification loop in plasmacytoid dendritic cells (pDCs), a specialized DC subset, for robust type I IFN release. S1PR1 agonist suppression is pertussis toxin-resistant, but inhibited by an S1PR1 C-terminal–derived transactivating transcriptional activator (Tat)-fusion peptide that blocks receptor internalization. S1PR1 agonist treatment accelerates turnover of IFNAR1, suppresses signal transducer and activator of transcription 1 (STAT1) phosphorylation, and down-modulates total STAT1 levels, thereby inactivating the autoamplification loop. Inhibition of S1P-S1PR1 signaling in vivo using the selective antagonist Ex26 significantly elevates IFN-α production in response to CpG-A. Thus, multiple lines of evidence demonstrate that S1PR1 signaling sets the sensitivity of pDC amplification of IFN responses, thereby blunting pathogenic immune responses. These data illustrate a lipid G-protein coupled receptor (GPCR)-IFNAR1 regulatory loop that balances effective and detrimental immune responses and elevated endogenous S1PR1 signaling. This mechanism will likely be advantageous in individuals subject to a range of inflammatory conditions.