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

Proceedings of the National Academy of Sciences of the United States of America
John R TeijaroHugh Rosen

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...Continue Reading

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Citations

Mar 3, 2018·Cellular Microbiology·Arielle M Bryan, Maurizio Del Poeta
Jan 10, 2018·Immunology·Matthew Collin, Venetia Bigley
Jun 11, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Madhuvanthi VijayanBumsuk Hahm
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Aug 6, 2021·Prostaglandins & Other Lipid Mediators·Jihua TianYun Zhou

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