title: Sirt6 regulates dendritic cell differentiation, maturation, and function.
abstract: Dendritic cells (DCs) are antigen-presenting cells that critically influence decisions about immune activation or tolerance. Impaired DC function is at the core of common chronic disorders and contributes to reduce immunocompetence during aging. Knowledge on the mechanisms regulating DC generation and function is necessary to understand the immune system and to prevent disease and immunosenescence. Here we show that the sirtuin Sirt6, which was previously linked to healthspan promotion, stimulates the development of myeloid, conventional DCs (cDCs). Sirt6-knockout (Sirt6KO) mice exhibit low frequencies of bone marrow cDC precursors and low yields of bone marrow-derived cDCs compared to wild-type (WT) animals. Sirt6KO cDCs express lower levels of class II MHC, of costimulatory molecules, and of the chemokine receptor CCR7, and are less immunostimulatory compared to WT cDCs. Similar effects in terms of differentiation and immunostimulatory capacity were observed in human monocyte-derived DCs in response to SIRT6 inhibition. Finally, while Sirt6KO cDCs show an overall reduction in their ability to produce IL-12, TNF-α and IL-6 secretion varies dependent on the stimulus, being reduced in response to CpG, but increased in response to other Toll-like receptor ligands. In conclusion, Sirt6 plays a crucial role in cDC differentiation and function and reduced Sirt6 activity may contribute to immunosenescence.
authors.affiliation: Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy.
authors.forename: Denise
authors.initials: D
authors.lastname: Lasigliè
authors.affiliation: The Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Boero
authors.affiliation: Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy.
authors.forename: Inga
authors.initials: I
authors.lastname: Bauer
authors.affiliation: Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16100 Genoa, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Morando
authors.affiliation: Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Damonte
authors.affiliation: Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Cea
authors.affiliation: Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy.|The Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy.
authors.forename: Fiammetta
authors.initials: F
authors.lastname: Monacelli
authors.affiliation: Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy.|The Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy.
authors.forename: Patrizio
authors.initials: P
authors.lastname: Odetti
authors.affiliation: Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy.|The Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ballestrero
authors.affiliation: The Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy.|Department of Neurology, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16100 Genoa, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Uccelli
authors.affiliation: The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114 USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
authors.affiliation: The Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poggi
authors.affiliation: Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy.|The Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Scientifico Tumori, Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Nencioni
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D005838:Genotype; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D000068884:Immunosenescence / Q000187:drug effects; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010641:Phenotype; D054400:Receptors, CCR7 / Q000276:immunology / Q000378:metabolism; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: C515371:Ccr7 protein, mouse; D000949:Histocompatibility Antigens Class II; D056572:Histone Deacetylase Inhibitors; D015850:Interleukin-6; D054400:Receptors, CCR7; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D018664:Interleukin-12; C501860:Sirt6 protein, mouse; D037761:Sirtuins
keywords: Sirt6; TNF-α; Toll-like receptor ligands; costimulatory molecules; dendritic cells; immunosenescence