Plasmacytoid dendritic cells and type I interferon as therapeutic cellular and molecular targets of autoimmune diseases

Abstract

Plasmacytoid dendritic cells (pDCs) play not only a central role in antiviral immune response in innate host defense but also a pathogenic role in the development of the autoimmune responses by vicious spiral based on the dysregulated type I IFN production through sensing immune complexes containing self-nucleic acids. Thus, type I IFNs and pDCs represent key molecular and cellular pathogenic components in autoimmune diseases such as systemic lupus erythematosus (SLE). Accordingly, control of the dysregulated pDC-derived type I IFN production provides an alternative treatment strategy for SLE. We focused on two agents, IκB kinase inhibitor (BAY11-7082) and HMG-CoA reductase inhibitors (statins), and investigated their immunomodulatory effects in targeting the IFN response on pDCs. Our study identified that both BAY11 and statins have the ability to inhibit nuclear translocation of IRF7 and IFN-α production in human pDCs. We also found that these agents inhibited both in vitro IFN-α production induced by the SLE serum and the in vivo serum IFN-α level induced by injecting mice with TLR ligand. These findings suggest that BAY11 and statins have the therapeutic potential to attenuate the IFN environment by regulating the pDC function and thus provide the novel foundation for the development of an effective immunotherapeutic strategy against autoimmune disorders such as SLE.