Editors' ChoiceImmunology

Interfering with interferons

Sci. Signal.  16 Feb 2016:
Vol. 9, Issue 415, pp. ec30
DOI: 10.1126/scisignal.aaf4271

Type I interferons (IFNs), which are mostly produced by plasmacytoid dendritic cells (pDCs), are critical to the immune response to viruses, but they are also implicated in autoimmune diseases and in viral and bacterial pathogenesis. Noting that selective agonists of sphingosine 1-phosphate receptor 1 (S1PR1), a G protein–coupled receptor (GPCR), suppress immunopathology without interfering with host defense, Teijaro et al. investigated the underlying mechanism. Treatment of mouse lung pDCs with the selective S1PR1 agonist CYM-5442 inhibited the production of IFN-α in response to influenza virus in vitro, whereas treatment with the S1PR1 antagonist W146 had the opposite effect. CYM-5442 also inhibited IFN-α production by pDCs in response to CpG oligonucleotides that trafficked to early endosomes and stimulated Toll-like receptor 9 (TLR9). Using pertussis toxin to block S1PR1-mediated activation of Gi/o proteins did not prevent CYM-5442 from inhibiting IFN-α production by pDCs exposed to influenza virus or CpG oligonucleotides. Without the type I IFN receptor IFNAR, pDCs cannot amplify IFN-α production and, as expected, IFNAR-deficient pDCs produced less IFN-α in response to CpG oligonucleotides than did wild-type pDCs. However, CYM-5442 had no further inhibitory effect on the IFNAR-deficient pDCs, suggesting that SIPR1 signaling blocks the autocrine amplification of type I IFN signaling rather than the initial production of IFN-α. Western blotting analysis showed that IFNAR abundance was reduced in CYM-5442–treated wild-type pDCs compared with that in W146-treated pDCs. Stimulation of pDCs with IFN-α in the presence of CYM-5442 resulted in decreased phosphorylation of the IFNAR effector STAT1 compared with that in W146-treated pDCs stimulated with IFN-α. Immunofluorescence confocal microscopy revealed that S1PR1 and IFNAR were colocalized to the plasma membrane in W146-treated pDCs, but were colocalized in lysosomes in response to CYM-5442. Compared with vehicle-treated mice, mice treated with an SIPR1 antagonist and then exposed to CpG oligonucleotides had increased amounts of serum IFN-α. Together, these data suggest that S1PR1 agonists prevent the amplification of IFN-α signaling and its associated immunopathology by promoting IFNAR internalization and degradation.

J. R. Teijaro, S. Studer, N. Leaf, W. B. Kiosses, N. Nguyen, K. Matsuki, H. Negishi, T. Taniguchi, M. B. A. Oldstone, H. Rosen, S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification. Proc. Natl. Acad. Sci. U.S.A. 113, 1351–1356 (2016). [PubMed]