title: Carbon monoxide impairs mitochondria-dependent endosomal maturation and antigen presentation in dendritic cells.
abstract: Heme-oxygenase 1 (HO-1) prevents T cell-mediated inflammatory disease by producing carbon monoxide (CO) and impairing DC immunogenicity. However, the cellular mechanisms causing this inhibition are unknown. Here, we show that CO impairs mitochondrial function in DCs by reducing both the mitochondrial membrane potential and ATP production, and resembling the effect of a nonlethal dose of a classical mitochondria uncoupler carbonyl cyanide m-chlorophenyl hydrazone (CCCP). Moreover, both CO and CCCP reduced cargo transport, endosome-to-lysosome fusion, and antigen processing, dampening the production of peptide-MHC complexes on the surface of DCs. As a result, the inhibition of naive CD4(+) T-cell priming was observed. Furthermore, mitochondrial dysfunction in DCs also significantly reduced CD8(+) T cell-dependent type 1 diabetes onset in vivo. These results showed for the first time that CO interferes with T-cell priming by blocking an unknown mitochondria-dependent antigen-processing pathway in mature DC. Interestingly, other immune functions in DCs such as antigen capture, cytokine secretion, costimulation, and cell survival relied on glycolysis, suggesting that oxidative phosphorylation might only play a key role for the maturation of antigen-containing endosomes. In conclusion, CO produced by HO-1 impairs antigen-dependent inflammation by regulating DC immunogenicity by a mitochondria-dependent mechanism.
authors.affiliation: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.|INSERM, UMR 1064, CHU Nantes, ITUN, Université de Nantes, Faculté de Médecine, Nantes, France.
authors.forename: Sebastián A
authors.initials: SA
authors.lastname: Riquelme
authors.affiliation: INSERM, UMR 1064, CHU Nantes, ITUN, Université de Nantes, Faculté de Médecine, Nantes, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Pogu
authors.affiliation: INSERM, UMR 1064, CHU Nantes, ITUN, Université de Nantes, Faculté de Médecine, Nantes, France.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Anegon
authors.affiliation: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.|INSERM, UMR 1064, CHU Nantes, ITUN, Université de Nantes, Faculté de Médecine, Nantes, France.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Bueno
authors.affiliation: Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.|INSERM, UMR 1064, CHU Nantes, ITUN, Université de Nantes, Faculté de Médecine, Nantes, France.|Departamento de Inmunología Clínica y Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Kalergis
mesh_terms: D017951:Antigen Presentation / Q000187:drug effects*; D002248:Carbon Monoxide / Q000494:pharmacology*; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology*; D011992:Endosomes / Q000502:physiology*; D051547:Heme Oxygenase-1 / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000502:physiology*
chemical_list: D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1
keywords: Antigen presentation; Carbon monoxide; Dendritic cell; Endosome; Heme-oxygenase 1; Mitochondria