Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2016 Feb 2;113(5):1351-6. doi: 10.1073/pnas.1525356113. Epub 2016 Jan 19.

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

Author information

1
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.
2
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;
3
Core Microscopy Facility, The Scripps Research Institute, La Jolla, CA 92037;
4
Department of Molecular Immunology, Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan.
5
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037; teijaro@scripps.edu mbaobo@scripps.edu hrosen@scripps.edu.
6
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037; teijaro@scripps.edu mbaobo@scripps.edu hrosen@scripps.edu.

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.

KEYWORDS:

IFNAR1; S1PR1; interferon-α; plasmacytoid dendritic cell; sphingosine 1-phosphate

PMID:
26787880
PMCID:
PMC4747766
DOI:
10.1073/pnas.1525356113
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center