Aryl hydrocarbon receptor negatively regulates type I interferon production and the development of murine lupus (CCR1P.245)

Abstract

Abstract Systemic lupus erythematosus is a highly heterogenous multi-organ autoimmune disease characterized by the production of diverse autoantibodies and a broad spectrum of clinical manifestations. The etiology and pathogenesis of lupus remain unclear. Our current understanding highlights an important role for autoantibodies and numerous studies in both animals and humans now suggest an important role for type I interferon (IFN) in the pathogenesis of lupus. Type I IFN signaling and subsequent feedback induction of type I IFN production, are critically dependent on the STAT1 transcription factor. How type I IFN activity is regulated through inhibition of STAT1 function is poorly understood. Here, we show that type I IFN production and signaling both in cultured plasmatoid dendritic cells, and in vivo, is significantly higher in Aryl hydrocarbon receptor (AHR) knockout mice compared to wild-type mice, following stimulation with TLR7/9 agonists. We demonstrate that through TLR7/9 signaling or by IFN-α, expression of AHR is induced, which in-turn forms an inhibitory interaction with STAT1. This interaction attenuates both type I IFN signaling and in-turn, positive-feedback induction of type I IFN. Furthermore, in pristane-induced murine lupus, we found that production of type I IFN and expression of IFN-stimulated genes in AHR knockout mice is higher than in wild-type mice. In conclusion, AHR negatively regulates type I IFN signaling and production and the development of murine lupus.