Aryl hydrocarbon receptor negatively regulates type I interferon production in murine lupus (P5225)

Abstract

Abstract Systemic lupus erythematosus is a multi-organ disorder characterized by the production of diverse autoantibodies. Recent studies suggest an important role for type I IFN in the pathogenesis of this disease. Production of type I IFN is induced by the transcription factor IRF7, while type I IFN signaling requires the STAT1 transcription factor. However, it is unclear how type I IFN is negatively regulated. Here, we show that production of type I IFN in cultured pDCs from aryl hydrocarbon receptor knockout mice is significantly higher compared to wild-type mice stimulated with TLR 7/9 agonists. Furthermore, treatment of pDCs from wild-type mice with the aryl hydrocarbon receptor agonist L-kynurenine significantly inhibits TLR 7/9-mediated type I IFN production. We demonstrate that through TLR 7/9 signaling, expression of aryl hydrocarbon receptor is induced, which in-turn forms an inhibitory interaction with IRF7 and STAT1, thus attenuating both type I IFN production and signaling. In addition, we found that production of type I IFN and expression of interferon stimulation genes in aryl hydrocarbon receptor knockout mice is higher than in wild-type mice when we induce lupus-like disease by pristane treatment. Our results suggest that aryl hydrocarbon receptor is a critical negative regulator of TLR-mediated type I IFN production and inhibits type I IFN signaling in murine lupus. We are evaluating protective effects of aryl hydrocarbon receptor agonists in murine lupus.