title: Inhibiting Oxidative Phosphorylation In Vivo Restrains Th17 Effector Responses and Ameliorates Murine Colitis.
abstract: Integration of signaling and metabolic pathways enables and sustains lymphocyte function. Whereas metabolic changes occurring during T cell activation are well characterized, the metabolic demands of differentiated T lymphocytes are largely unexplored. In this study, we defined the bioenergetics of Th17 effector cells generated in vivo. These cells depend on oxidative phosphorylation (OXPHOS) for energy and cytokine production. Mechanistically, the essential role of OXPHOS in Th17 cells results from their limited capacity to increase glycolysis in response to metabolic stresses. This metabolic program is observed in mouse and human Th17 cells, including those isolated from Crohn disease patients, and it is linked to disease, as inhibiting OXPHOS reduces the severity of murine colitis and psoriasis. These studies highlight the importance of analyzing metabolism in effector lymphocytes within in vivo inflammatory contexts and suggest a therapeutic role for manipulating OXPHOS in Th17-driven diseases.
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Luigi
authors.initials: L
authors.lastname: Franchi
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Ivan
authors.initials: I
authors.lastname: Monteleone
authors.affiliation: Lycera Corporation, Ann Arbor, MI 48109.
authors.forename: Ling-Yang
authors.initials: LY
authors.lastname: Hao
authors.affiliation: Lycera Corporation, Ann Arbor, MI 48109.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Spahr
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Wenpu
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Lycera Corporation, Ann Arbor, MI 48109.
authors.forename: Xikui
authors.initials: X
authors.lastname: Liu
authors.affiliation: Lycera Corporation, Ann Arbor, MI 48109.
authors.forename: Kellie
authors.initials: K
authors.lastname: Demock
authors.affiliation: Lycera Corporation, Ann Arbor, MI 48109.
authors.forename: Aditi
authors.initials: A
authors.lastname: Kulkarni
authors.affiliation: Lycera Corporation, Ann Arbor, MI 48109.
authors.forename: Chuck A
authors.initials: CA
authors.lastname: Lesch
authors.affiliation: Lycera Corporation, Ann Arbor, MI 48109.
authors.forename: Brian
authors.initials: B
authors.lastname: Sanchez
authors.affiliation: Lycera Corporation, Ann Arbor, MI 48109.
authors.forename: Laura
authors.initials: L
authors.lastname: Carter
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Marafini
authors.affiliation: Lycera Corporation, Ann Arbor, MI 48109.
authors.forename: Xiao
authors.initials: X
authors.lastname: Hu
authors.affiliation: Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Oksana
authors.identifier: 0000-0003-4960-9696
authors.initials: O
authors.lastname: Mashadova
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02115.
authors.forename: Min
authors.identifier: 0000-0002-2178-5017
authors.initials: M
authors.lastname: Yuan
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA 02115.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.
authors.forename: Harinder
authors.initials: H
authors.lastname: Singh
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109.|Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Costas A
authors.identifier: 0000-0001-9309-6141
authors.initials: CA
authors.lastname: Lyssiotis
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
authors.affiliation: Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, 48109; and.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Opipari
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor, MI 48109 gglick@umich.edu.
authors.forename: Gary D
authors.identifier: 0000-0003-0959-3749
authors.initials: GD
authors.lastname: Glick
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D003092:Colitis / Q000276:immunology*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010085:Oxidative Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D058504:Th17 Cells / Q000276:immunology*; D059467:Transcriptome