Aryl hydrocarbon receptor restrains tonic cytokine responses by inhibiting microbiota sensing in monocytes

Immune cells are constantly exposed to microbiota-derived compounds that can engage innate recognition receptors. How this constitutive stimulation is downmodulated to avoid systemic inflammation and autoimmunity is poorly understood. Here, we show that aryl hydrocarbon receptor (AhR) deficiency in monocytes unleashed spontaneous cytokine responses in vivo, driven by stimulator of interferon genes (STING)-mediated tonic sensing of microbiota. This effect was specific to monocytes, as mice deficient for AhR specifically in macrophages did not show any dysregulation of tonic cytokine responses. AhR inhibition also increased tonic cytokine production in human monocytes. Finally, in patients with systemic juvenile idiopathic arthritis, low AhR activity in monocytes correlated with elevated cytokine responses. Our findings reveal an essential role for AhR in monocytes in restraining tonic microbiota sensing and in maintaining immune homeostasis.