title: Mitochondrial H2O2 in Lung Antigen-Presenting Cells Blocks NF-κB Activation to Prevent Unwarranted Immune Activation.
abstract: 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.
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Western Michigan University Homer Stryker School of Medicine, Kalamazoo, MI 49008, USA.
authors.forename: Anupriya
authors.initials: A
authors.lastname: Khare
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Western Michigan University Homer Stryker School of Medicine, Kalamazoo, MI 49008, USA.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Raundhal
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Western Michigan University Homer Stryker School of Medicine, Kalamazoo, MI 49008, USA.
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Chakraborty
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Western Michigan University Homer Stryker School of Medicine, Kalamazoo, MI 49008, USA.
authors.forename: Sudipta
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Pharmacology and Chemical Biology, Western Michigan University Homer Stryker School of Medicine, Kalamazoo, MI 49008, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Corey
authors.affiliation: Department of Pharmacology and Chemical Biology, Western Michigan University Homer Stryker School of Medicine, Kalamazoo, MI 49008, USA.
authors.forename: Christelle K
authors.initials: CK
authors.lastname: Kamga
authors.affiliation: Department of Biomedical Sciences, Western Michigan University Homer Stryker School of Medicine, Kalamazoo, MI 49008, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Quesnelle
authors.affiliation: Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Claudette
authors.initials: C
authors.lastname: St Croix
authors.affiliation: Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Western Michigan University Homer Stryker School of Medicine, Kalamazoo, MI 49008, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Morse
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Western Michigan University Homer Stryker School of Medicine, Kalamazoo, MI 49008, USA.
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Oriss
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Western Michigan University Homer Stryker School of Medicine, Kalamazoo, MI 49008, USA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Huff
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Western Michigan University Homer Stryker School of Medicine, Kalamazoo, MI 49008, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Hannum
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Western Michigan University Homer Stryker School of Medicine, Kalamazoo, MI 49008, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Prabir
authors.initials: P
authors.lastname: Ray
authors.affiliation: Department of Pharmacology and Chemical Biology, Western Michigan University Homer Stryker School of Medicine, Kalamazoo, MI 49008, USA; Vascular Medical Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Sruti
authors.initials: S
authors.lastname: Shiva
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Western Michigan University Homer Stryker School of Medicine, Kalamazoo, MI 49008, USA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. Electronic address: raya@pitt.edu.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Ray
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D039521:CD11c Antigen / Q000378:metabolism; D049109:Cell Proliferation; D016207:Cytokines / Q000235:genetics; D003713:Dendritic Cells / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007108:Immune Tolerance; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000166:cytology*; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D047495:PPAR gamma / Q000172:deficiency / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology
chemical_list: D039521:CD11c Antigen; D016207:Cytokines; D005227:Fatty Acids; D018836:Inflammation Mediators; D016328:NF-kappa B; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide