111: Aryl hydrocarbon receptor negatively regulates type I interferon production and the development of murine lupus

Abstract

Background Systemic lupus erythematosus is a highly heterogenous multi-organ autoimmune disease characterized by the production of diverse autoantibodies and broad spectrum of clinical manifestations. Various studies 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. However, how type I IFN activity is regulated through inhibition of STAT1 function is poorly understood. In our previous study we demonstrated that the aryl hydrocarbon receptor (AHR) inhibits STAT1 activity through TLR4 signaling. In the current study we investigated a role for AHR in type I IFN signaling through TLR7/9 pathways. Methods and results We showed that type I IFN production and signaling both in plasmacytoid dendritic cells (pDCs), and in vivo , is significantly higher in AHR knockout mice compared to wild-type mice, following stimulation with TLR9 ligands. Type I IFN production was suppressed by AHR agonist and in AHR over-expressing cells. We demonstrated that through TLR9 signaling or by IFN-α stimulation in pDCs, 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. Interestingly, we also found that AHR also forms an inhibitory interaction with IRF7 (a transcription factor which induces type I IFN production). In pristane-induced murine lupus, we found that expression of IFN-stimulated genes, accumulation of Ly6c high IFN producing cells, production of type I IFN-dependent autoantibody and severity of proteinurea, were significantly higher in AHR knockout mice compared to wild-type mice. Conclusion We firstly report that AHR negatively regulates type I IFN production and signaling through an inhibitory interaction with IRF7 and STAT1 respectively and inhibits interferon-dependent disease in murine lupus.