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 downmodulates 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. sphingosine 1-phosphate | S1PR1 | plasmacytoid dendritic cell | interferon-α | IFNAR1

Sphingosine 1-Phosphate Lyase Enhances the Activation of IKKε To Promote Type I IFN–Mediated Innate Immune Responses to Influenza A Virus Infection

“…However, the sphingosine analogs or S1P 1 R agonist could regulate cytokine responses during influenza virus infection (57–60). Also, it was recently reported that the agonist of S1P 1 R or exogenous S1P can directly induces degradation of type I IFN receptor (IFNAR) to inhibit IFN amplification on plasmacytoid dendritic cells (61). This could be an important mechanism for the regulation of inflammatory response, given that S1P has been shown to affect cytokine/chemokine responses in diverse conditions (62–64).…”

IL-1β expression is increased and regulates GABA transmission following chronic ethanol in mouse central amygdala

“…Auto-traced outlines of the cells were used as regions of interest from which the total signal above background was extracted for the IL-1β signal. The total cellular area and mean fluorescence intensity of IL-1β in each cell was scored and plotted as integrated density (ID) (average area × mean fluorescence intensity/100), which was estimated separately for approximately 800 neurons and 200 microglial cells per section The average ID/cell per section for 3–4 sections from each mouse, containing both the left and right hemisphere CeA, was used for statistical analysis and graphing 47–50 .…”

Progression of type 1 diabetes from the prediabetic stage is controlled by interferon-α signaling

“…4H). Thus, S1PR1 agonist prevented T1D by suppressing IFN-α signaling (20,24), restricting the migration of antiself T cells to geographic areas outside the islets and likely by contributing to T-cell exhaustion through up-regulation of negative immune regulators like PD-1 and LAG3.…”

“…Sphingosine-1-phosphate receptor 1 (S1PR1) agonists like CYM-5442 modulate lymphocyte trafficking and significantly alter IFN-α autoamplification acting primarily on pDCs to reduce IFN-α expression by promoting the turnover of IFNAR at the cell surface, resulting in reduced STAT1 phosphorylation and inhibition of type I IFN autoamplification (20). To determine whether modulation of the S1PR1 signaling would abort the development of T1D, Rip-LCMV tg mice infected with virus and receiving daily administration of CYM-5442 (10 mg/kg) showed normal blood glucose levels over a 21-d observation period compared with isotype control in which four out of five mice displayed diabetic levels (>250 mg/dL) by day 10 p.i.…”

“…Importantly, CYM-5442 blocks not all but ∼80-90% of type I IFN, thereby maintaining sufficient IFN-α to generate CTLs and antibodies to combat viral infections (20,24,26), while preventing T1D. Fourth, CYM-5442 therapy enhanced the expression of negative immune regulating surface molecules on autoreactive T cells, further limiting the ability of any autoimmune T-cell that might enter the islets from killing β cells.…”