Sphingosine analog AAL-R enhances TLR7-mediated dendritic cell activation via p38 MAPK and type I IFN signaling pathways (180.12)

Abstract

Abstract Sphingosine analogs display immunosuppressive activities and are therapeutically used for the treatment of autoimmune diseases. Here, we investigated the effects of the sphingosine analog AAL-R (FTY720 derivative) on dendritic cell (DC) response to toll-like receptor (TLR) stimulation. AAL-R inhibited DC maturation in response to TLR3 or TLR4 activation, representing its previously known immunosuppressive action. In contrast, AAL-R increased TLR7-mediated DC responses by increasing the expression of MHC-I and co-stimulatory molecules and type I interferon (IFN), and by enhancing the capacity of DCs to induce CD8+ T cell proliferation. Importantly, the stimulatory activity of AAL-R was dependent on type I IFN signaling, since type I IFN receptor-deficient DCs failed to respond to AAL-R. Further, AAL-R activated p38 MAPK signaling to increase type I IFN synthesis and TLR7-mediated DC maturation. Thus, our results indicate that AAL-R’s regulatory action is strongly affected by the form of pathogenic molecular patterns and is stimulatory when DCs are treated with a TLR7 agonist. These findings enhance our understanding of sphingosine regulation of host immune responses particularly in pathogenic infections.