title: S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification.
abstract: 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.
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037; teijaro@scripps.edu mbaobo@scripps.edu hrosen@scripps.edu.
authors.forename: John R
authors.initials: JR
authors.lastname: Teijaro
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Sean
authors.initials: S
authors.lastname: Studer
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Nora
authors.initials: N
authors.lastname: Leaf
authors.affiliation: Core Microscopy Facility, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: William B
authors.initials: WB
authors.lastname: Kiosses
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;
authors.forename: Nhan
authors.initials: N
authors.lastname: Nguyen
authors.affiliation: Department of Molecular Immunology, Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Matsuki
authors.affiliation: Department of Molecular Immunology, Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Negishi
authors.affiliation: Department of Molecular Immunology, Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan.
authors.forename: Tadatsugu
authors.initials: T
authors.lastname: Taniguchi
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; teijaro@scripps.edu mbaobo@scripps.edu hrosen@scripps.edu.
authors.forename: Michael B A
authors.initials: MB
authors.lastname: Oldstone
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037; teijaro@scripps.edu mbaobo@scripps.edu hrosen@scripps.edu.
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000378:metabolism*; D016898:Interferon-alpha / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D059748:Proteolysis; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000502:physiology*
chemical_list: C507964:IFNAR1 protein, human; D016898:Interferon-alpha; D049349:Receptors, Lysosphingolipid; D053633:Receptor, Interferon alpha-beta
keywords: IFNAR1; S1PR1; interferon-α; plasmacytoid dendritic cell; sphingosine 1-phosphate