Apoptotic cell induced, TLR9-dependent AhR activity is required for immunologic tolerance and suppression of lupus

The Aryl hydrocarbon receptor (AhR) can potently modulate immunity at multiple levels, but its mechanistic role in immune regulation is still being elucidated. Here we show phagocytes exposed to apoptotic cells exhibit rapid activation of AhR driving IL-10 that antagonizes inflammatory cytokine production. AhR activation was dependent on apoptotic cell DNA-TLR9 interactions and reactive oxygen species production in phagocytes that promoted nuclear accumulation and transcriptional activity. In vivo, apoptotic cell-induced AhR signals in myeloid cells were required for prevention of inflammatory innate and adaptive immunity against DNA and histones. Moreover, disease progression in lupus correlated with AhR signal strength, and disease course could be reduced or exacerbated by modulation of AhR activity. Finally we observed myeloid lineage AhR deletion caused systemic autoimmunity, and in SLE patients an increased AhR transcriptional signature correlated with disease. Thus our findings suggest AhR activity influenced by apoptotic cell death is a key mechanism in maintenance of peripheral tolerance reducing inflammation and thereby retarding systemic autoimmune disease progression.