Mitochondrial H2O2 in Lung Antigen-Presenting Cells Blocks NF-κB Activation to Prevent Unwarranted Immune Activation

Inhalation of environmental antigens such as allergens does not always induce inflammation in the respiratory tract. While antigen-presenting cells (APCs), including dendritic cells and macrophages, take up inhaled antigens, the cell-intrinsic molecular mechanisms that prevent an inflammatory response during this process, such as activation of the transcription factor NF-κB, are not well understood. Here, we show that the nuclear receptor PPARγ plays a critical role in blocking NF-κB activation in response to inhaled antigens to preserve immune tolerance. Tolerance induction promoted mitochondrial respiration, generation of H2O2, and suppression of NF-κB activation in WT, but not PPARγ-deficient, APCs. Forced restoration of H2O2 in PPARγ-deficient cells suppressed IκBα degradation and NF-κB activation. Conversely, scavenging reactive oxygen species from mitochondria promoted IκBα degradation with loss of regulatory and promotion of inflammatory T cell responses in vivo. Thus, communication between PPARγ and the mitochondria maintains immune quiescence in the airways. [Display omitted] •Immune tolerance invokes PPARγ-dependent mitochondrial H2O2 in lung immune cells•PPARγ promotes superoxidase dismutase expression, which is central to H2O2 generation•PPARγ-dependent mitochondrial H2O2 inhibits NF-κB activation to suppress inflammation•PPARγ links the nucleus, mitochondria, and cell cytoplasm to ensure immune quiescence Khare et al. describe an essential role of PPARγ in maintenance of immune tolerance. Tolerance induction by inhaled antigen promotes PPARγ-dependent H2O2 generation in lung dendritic cells and macrophages involving mitochondrial metabolism requiring complex I activity. H2O2 suppresses NF-κB activation to prevent inflammatory T cell responses but supports Treg generation.