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S1PR1-Mediated IFNAR1 Degradation Modulates Plasmacytoid Dendritic Cell Interferon-Α Autoamplification

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S1PR1-Mediated IFNAR1 Degradation Modulates Plasmacytoid Dendritic Cell Interferon-Α Autoamplification S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification John R. Teijaroa,b,1,2, Sean Studerb,1, Nora Leafb, William B. Kiossesc, Nhan Nguyenb, Kosuke Matsukid, Hideo Negishid, Tadatsugu Taniguchid, Michael B. A. Oldstonea,2, and Hugh Rosenb,2 aDepartment of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; bDepartment of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037; cCore Microscopy Facility, The Scripps Research Institute, La Jolla, CA 92037; and dDepartment of Molecular Immunology, Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan Contributed by Michael B. A. Oldstone, December 23, 2015 (sent for review November 16, 2015; reviewed by Arturo Casadevall and Herbert W. Virgin) Blunting immunopathology without abolishing host defense is the curb resulting immune pathology during both infectious and foundation for safe and effective modulation of infectious and autoimmune disease states. autoimmune diseases. Sphingosine 1-phosphate receptor 1 (S1PR1) The goal of the current study was to generate a detailed mech- agonists are effective in treating infectious and multiple autoimmune anistic understanding of how S1PR1 selectively suppresses type I pathologies; however, mechanisms underlying their clinical efficacy IFN and cytokine amplification. Within this study, we demonstrate are yet to be fully elucidated. Here, we uncover an unexpected that S1PR1 signaling limits the IFN-α autoamplification loop in mechanism of convergence between S1PR1 and interferon alpha pDCs. S1PR1 agonist suppression is pertussis toxin (PT)-resistant, receptor 1 (IFNAR1) signaling pathways. Activation of S1PR1 signaling but it is inhibited by an S1PR1 C-terminal–derived transactivating by pharmacological tools or endogenous ligand sphingosine-1 phos- transcriptional activator (Tat)-fusion peptide that blocks receptor phate (S1P) inhibits type 1 IFN responses that exacerbate numerous internalization. S1PR1 agonist treatment accelerates turnover of pathogenic conditions. Mechanistically, S1PR1 selectively suppresses interferon alpha receptor 1 (IFNAR1), suppresses signal transducer the type I IFN autoamplification loop in plasmacytoid dendritic cells and activator of transcription 1 (STAT1) phosphorylation, and down- (pDCs), a specialized DC subset, for robust type I IFN release. S1PR1 modulates total STAT1 levels, thereby inactivating the autoamplifi- agonist suppression is pertussis toxin-resistant, but inhibited by an cation loop. Inhibition of S1P-S1PR1 signaling in vivo using the S1PR1 C-terminal–derived transactivating transcriptional activator selective antagonist Ex26 significantly elevates IFN-α production in (Tat)-fusion peptide that blocks receptor internalization. S1PR1 agonist response to CpG-A. Thus, multiple lines of evidence demonstrate treatment accelerates turnover of IFNAR1, suppresses signal transducer that S1PR1 signaling sets the sensitivity of pDC amplification of IFN and activator of transcription 1 (STAT1) phosphorylation, and down- responses, thereby blunting pathogenic immune responses. modulates total STAT1 levels, thereby inactivating the autoamplifica- tion loop. Inhibition of S1P-S1PR1 signaling in vivo using the selective Results antagonist Ex26 significantly elevates IFN-α production in response to To understand how S1PR1 signaling regulates IFN-α and cyto- CpG-A. Thus, multiple lines of evidence demonstrate that S1PR1 signal- kine amplification, we assessed the pulmonary cell subsets that ing sets the sensitivity of pDC amplification of IFN responses, thereby produce IFN-α and cytokines/chemokines following influenza blunting pathogenic immune responses. These data illustrate a lipid virus challenge. Although many cell types produce IFN-α G-protein coupled receptor (GPCR)-IFNAR1 regulatory loop that bal- following virus infection, two major pulmonary cell populations ances effective and detrimental immune responses and elevated en- dogenous S1PR1 signaling. This mechanism will likely be advantageous Significance in individuals subject to a range of inflammatory conditions. The sphingosine 1-phosphate receptor (S1PR1) is known to act by sphingosine 1-phosphate | S1PR1 | plasmacytoid dendritic cell | multiple mechanisms: limiting lymphocyte egress from secondary interferon-α | IFNAR1 lymphoid organs, suppressing proinflammatory endothelial cell function, and acting directly on neurons and astrocytes. Here, we lasmacytoid dendritic cells (pDCs) are a rare innate immune report that sphingosine 1-phosphate (S1P)-S1PR1 signaling in Pcell population in mice known for their ability to produce plasmacytoid dendritic cells (pDCs) directly inhibits IFN-α auto- large quantities of type 1 IFN (IFN-I) following stimulation with amplification by induced degradation of the interferon alpha re- viral or cellular nucleic acids. Moreover, IFN-α signaling promotes ceptor 1 (IFNAR1) receptor and suppression of signal transducer autoimmune (1), viral (2–5), and bacterial disease pathogenesis and activator of transcription 1 (STAT1) signaling. An endosomal (6). Suppression of IFN-α signaling has demonstrated efficacy in regulatory interaction of a lipid G-protein coupled receptor (GPCR) multiple autoimmune mouse models (7–9) and during influenza and IFNAR1 balances effective and detrimental components of viral infection (4, 10); however, the mechanism by which sphin- immune responses and provides a previously unidentified path- gosine 1-phosphate receptor 1 (S1PR1) signaling prevents IFN-α way that contributes to significant and unexpected efficacy in clinical trials in multiple sclerosis, ulcerative colitis, psoriasis, and amplification during these disease states is currently unknown. likely other diseases with aberrant IFN-α signatures. Recently, we found direct evidence that IFN-I induction and the concomitant cytokine storm were chemically tractable using Author contributions: J.R.T., S.S., T.T., M.B.A.O., and H.R. designed research; J.R.T., S.S., sphingosine 1-phosphate receptor 1 (S1PR1) selective agonists. N.L., W.B.K., N.N., K.M., and H.N. performed research; J.R.T., S.S., T.T., M.B.A.O., and H.R. S1PR1 agonist therapy suppressed innate immune cell recruit- analyzed data; and J.R.T., S.S., M.B.A.O., and H.R. wrote the paper. ment and cytokine-chemokine production and improved survival Reviewers: A.C., Johns Hopkins Bloomberg School of Public Health; and H.W.V., Washington University. without postponing viral clearance, indicating that cytokine The authors declare no conflict of interest. storm was causative of disease pathogenesis and that S1P agonist 1J.R.T. and S.S. contributed equally to this work. therapy could suppress detrimental innate immune responses 2To whom correspondence may be addressed. Email: [email protected], mbaobo@ without hindering virus control (10, 11). The identification that scripps.edu, or [email protected]. S1PR1 agonists suppress detrimental innate immune responses This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. INFLAMMATION IMMUNOLOGY AND indicates that S1PR1 probes may serve as viable drug leads to 1073/pnas.1525356113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1525356113 PNAS | February 2, 2016 | vol. 113 | no. 5 | 1351–1356 Downloaded by guest on October 2, 2021 make significant quantities of IFN-α in vivo following respiratory through TLR7 signaling, we asked if CYM-5442 could also virus infection, alveolar macrophages and pDCs (11); thus, we modulate TLR9 signaling in pDCs. Two classes of immunosti- initially focused on these populations. We depleted pDCs from mulatory oligonucleotides were demonstrated to activate pDCs mice before influenza virus challenge. Depletion of pDCs before differentially through TLR9 stimulation (14, 15). Treatment of influenza virus challenge significantly reduced IFN-α levels fol- pDC with CpG-A or influenza virus resulted in elevated IFN-α lowing influenza virus infection, as well as CCL2, CCL5, and IL-6 secretion similar to previous reports, and treatment with CYM- levels (Fig. S1). We asked whether treatment of fluorescence- 5442 inhibited IFN-α induction upon both CpG-A and influenza activated cell sorter (FACS)–purified pDCs (>90%) from the virus stimulation (Fig. 2A). Surprisingly, treatment with CYM- spleen or lung with the selective S1PR1 agonist CYM-5442 5442 had no effect following CpG-B stimulation (Fig. 2A), sug- (Table 1) could inhibit the production of IFN-α following stim- gesting that S1PR1 agonist targets suppression of TLR9 signal- ulation with influenza virus in vitro. Infection of pDCs with in- ing in the early endosome. Further, CYM-5442 treatment of fluenza virus followed by CYM-5442 treatment resulted in the pDCs isolated from the peripheral blood of human donors dis- α A μ inhibition of IFN- production (Fig. 1 )atanIC50 of 1.4 M, as played similar suppressive capacity following CpG-A stimulation well as an IC50 of 500 nM using the highly potent S1PR1 agonist and no effect following CpG-B stimulation (Fig. 2B). Because RP-001 (11), demonstrating direct inhibition of IFN-α pro- CpG-A and CpG-B are known to localize to different in- duction from pDCs by S1PR1 agonists. Interestingly, the IC50 of tracellular compartments (14), we asked whether S1PR1 agonist- S1PR1 agonist CYM-5442 required to inhibit IFN-α amplifica- mediated suppression was specific to endosome signaling in tion exceeds the IC50 required to activate Gi/Go signaling, sug-
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