title: Sirtuin 1 Regulates Dendritic Cell Activation and Autophagy during Respiratory Syncytial Virus-Induced Immune Responses.
abstract: Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in children worldwide. Sirtuin 1 (SIRT1), an NAD(+)-dependent deacetylase, has been associated with the induction of autophagy and the regulation of inflammatory mediators. We found that Sirt1 was upregulated in mouse lung after RSV infection. Infected animals that received EX-527, a selective SIRT1 inhibitor, displayed exacerbated lung pathology, with increased mucus production, elevated viral load, and enhanced Th2 cytokine production. Gene expression analysis of isolated cell populations revealed that Sirt1 was most highly upregulated in RSV-treated dendritic cells (DCs). Upon RSV infection, EX-527-treated DCs, Sirt1 small interfering RNA-treated DCs, or DCs from conditional knockout (Sirt1(f/f)-CD11c-Cre(+)) mice showed downregulated inflammatory cytokine gene expression and attenuated autophagy. Finally, RSV infection of Sirt1(f/f)-CD11c-Cre(+) mice resulted in altered lung and lymph node cytokine responses, leading to exacerbated pathology. These data indicate that SIRT1 promotes DC activation associated with autophagy-mediated processes during RSV infection, thereby directing efficient antiviral immune responses.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and.
authors.forename: Anna B
authors.initials: AB
authors.lastname: Owczarczyk
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Schaller
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and.
authors.forename: Michelle
authors.initials: M
authors.lastname: Reed
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rasky
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and Institute of Gerontology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: David B
authors.initials: DB
authors.lastname: Lombard
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and nlukacs@med.umich.edu.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Lukacs
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D002227:Carbazoles / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D015870:Gene Expression; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D002227:Carbazoles; D016207:Cytokines; D056564:Sirtuin 1