Apoptotic cell driven ROS burst drives AhR dependent immunologic tolerance and suppression of lupus

Tissue-resident macrophages (MΦ) are crucial in driving tolerance and preventing systemic autoimmunity. We have previously shown that exposure to apoptotic cells triggers a regulatory circuit dependent on IL-10 production in resident MΦ. However, key molecular mechanisms driving the regulatory response to apoptosis are not clear. RNA transcriptome analysis of MΦs after exposure to apoptotic cells identified strong transcript association with the aryl hydrocarbon receptor (AhR) signaling pathway, an association that was confirmed by phenotypic and biochemical analysis. When AhR activity was blocked, apoptotic cells induced an alteration in the mRNA signature enhancing proinflammatory effector expression. Functional analysis revealed that the DNA from apoptotic cells activated AhR in a reactive oxygen species (ROS) dependent mechanism and AhR is required for IL-10 production. Consequently, inhibition or deletion of AhR signals fundamentally altered immune responses to apoptotic cells in vivo resulting in proinflammatory cytokine production, increased effector T cell responses, and failure of long-term tolerance to apoptotic cell-associated antigens. Surprisingly, mice lacking AhR developed progressive systemic autoimmunity characterized by excessive MΦ and lymphocyte activation and renal pathology. Similarly, SLE-prone mice treated with AhR antagonist exhibited poor survival, while agonist treatment ablated disease pathology. Finally, an AhR transcriptional signature was significantly associated with active SLE flare in SLE patients. Thus, the data demonstrates the AhR pathway is a key molecular circuit responsible for apoptotic cell driven tolerance and suppression of inflammatory autoimmunity.