title: Cutting Edge: Dual Function of PPARγ in CD11c+ Cells Ensures Immune Tolerance in the Airways.
abstract: The respiratory tract maintains immune homeostasis despite constant provocation by environmental Ags. Failure to induce tolerogenic responses to allergens incites allergic inflammation. Despite the understanding that APCs have a crucial role in maintaining immune tolerance, the underlying mechanisms are poorly understood. Using mice with a conditional deletion of peroxisome proliferator-activated receptor γ (PPARγ) in CD11c(+) cells, we show that PPARγ performs two critical functions in CD11c(+) cells to induce tolerance, thereby preserving immune homeostasis. First, PPARγ was crucial for the induction of retinaldehyde dehydrogenase (aldh1a2) selectively in CD103(+) dendritic cells, which we recently showed promotes Foxp3 expression in naive CD4(+) T cells. Second, in all CD11c(+) cells, PPARγ was required to suppress expression of the Th17-skewing cytokines IL-6 and IL-23p19. Also, lack of PPARγ in CD11c(+) cells induced p38 MAPK activity, which was recently linked to Th17 development. Thus, PPARγ favors immune tolerance by promoting regulatory T cell generation and blocking Th17 differentiation.
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and.
authors.forename: Anupriya
authors.initials: A
authors.lastname: Khare
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and.
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Chakraborty
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Raundhal
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.
authors.forename: Prabir
authors.initials: P
authors.lastname: Ray
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 raya@pitt.edu.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Ray
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000276:immunology; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D039521:CD11c Antigen / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D006706:Homeostasis; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007108:Immune Tolerance; D007113:Immunity, Innate; D039001:Integrin alpha Chains / Q000235:genetics / Q000276:immunology; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics / Q000276:immunology*; D012137:Respiratory System / Q000276:immunology* / Q000473:pathology; D050697:Retinal Dehydrogenase; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology
chemical_list: D015703:Antigens, CD; D039521:CD11c Antigen; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D039001:Integrin alpha Chains; D053760:Interleukin-23 Subunit p19; D015850:Interleukin-6; D047495:PPAR gamma; C091367:alpha E integrins; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C512722:Aldh1a2 protein, mouse; D050697:Retinal Dehydrogenase; D048051:p38 Mitogen-Activated Protein Kinases