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-kappa B, are not well understood. Here, we show that the nuclear receptor PPAR gamma plays a critical role in blocking NF-kappa B activation in response to inhaled antigens to preserve immune tolerance. Tolerance induction promoted mitochondrial respiration, generation of H2O2, and suppression of NF kappa B activation in WT, but not PPAR gamma-deficient, APCs. Forced restoration of H2O2 in PPAR gamma-deficient cells suppressed I kappa B alpha degradation and NF-kappa B activation. Conversely, scavenging reactive oxygen species from mitochondria promoted I kappa B alpha degradation with loss of regulatory and promotion of inflammatory T cell responses in vivo. Thus, communication between PPAR gamma and the mitochondria maintains immune quiescence in the airways.