160 : Aryl hydrocarbon receptor negatively regulates type I interferon signaling in the development of murine lupus

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 interferon signaling in the pathogenesis of this disease. Type I interferon signaling requires the STAT1 transcription factor. How STAT1 activity is negatively regulated by type-I IFN is poorly understood. We show that induction of type I interferon-stimulated genes in cultured pDCs from aryl hydrocarbon receptor knockout mice is significantly higher compared to wild-type mice stimulated with toll-like receptor 7/9 agonists. Treatment of pDCs from wild-type mice with the aryl hydrocarbon receptor agonist L-kynurenine significantly inhibits toll-like receptor 7/9-mediated type I interferon signaling. We demonstrate that through toll-like receptor 7/9 signaling, expression of aryl hydrocarbon receptor is induced, which in-turn forms an inhibitory interaction with STAT1, thus attenuating type I interferon signaling. In addition, expression of interferon stimulated genes in aryl hydrocarbon receptorknockout mice, is higher than in wild-type mice during pristane-induced murine lupus. Our results show that aryl hydrocarbon receptor is a critical negative regulator of toll-like receptor-mediated type I interferon signaling through its interaction with STAT1, and inhibits type I interferon signaling in murine lupus. We are currently evaluating protective effects of aryl hydrocarbon receptor agonists in the development of murine lupus.