title: AMP-Activated Protein Kinase Suppresses Autoimmune Central Nervous System Disease by Regulating M1-Type Macrophage-Th17 Axis.
abstract: The AMP-activated protein kinase, AMPK, is an energy-sensing, metabolic switch implicated in various metabolic disorders; however, its role in inflammation is not well defined. We have previously shown that loss of AMPK exacerbates experimental autoimmune encephalomyelitis (EAE) disease severity. In this study, we investigated the mechanism through which AMPK modulates inflammatory disease like EAE. AMPKα1 knockout (α1KO) mice with EAE showed severe demyelination and inflammation in the brain and spinal cord compared with wild-type due to higher expression of proinflammatory Th17 cytokines, including IL-17, IL-23, and IL-1β, impaired blood-brain barrier integrity, and increased infiltration of inflammatory cells in the CNS. Infiltrated CD4 cells in the brains and spinal cords of α1KO with EAE were significantly higher compared with wild-type EAE and were characterized as IL-17 (IL-17 and GM-CSF double-positive) CD4 cells. Increased inflammatory response in α1KO mice was due to polarization of macrophages (Mϕ) to proinflammatory M1 type phenotype (IL-10(low)IL-23/IL-1β/IL-6(high)), and these M1 Mϕ showed stronger capacity to induce allogenic as well as Ag-specific (myelin oligodendrocyte glycoprotein [MOG]35-55) T cell response. Mϕ from α1KO mice also enhanced the encephalitogenic property of MOG35-55-primed CD4 T cells in B6 mice. The increased encephalitogenic MOG-restricted CD4(+) T cells were due to an autocrine effect of IL-1β/IL-23-mediated induction of IL-6 production in α1KO Mϕ, which in turn induce IL-17 and GM-CSF production in CD4 cells. Collectively, our data indicate that AMPK controls the inflammatory disease by regulating the M1 phenotype-Th17 axis in an animal model of multiple sclerosis.
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
authors.forename: Ashutosh K
authors.identifier: 0000-0002-9926-2531
authors.initials: AK
authors.lastname: Mangalam
authors.affiliation: Division of Gynecologic Oncology, Department of Women's Health Services, Henry Ford Health System, Detroit, MI 48202;
authors.forename: Ramandeep
authors.initials: R
authors.lastname: Rattan
authors.affiliation: Department of Neurology, Henry Ford Health System, Detroit, MI 48202;
authors.forename: Hamid
authors.initials: H
authors.lastname: Suhail
authors.affiliation: Department of Neurology, Henry Ford Health System, Detroit, MI 48202;
authors.forename: Jaspreet
authors.initials: J
authors.lastname: Singh
authors.affiliation: Department of Medical Laboratory, Imaging and Radiologic Sciences, Augusta University, Augusta, GA 30912; Department of Neurology, Augusta University, Augusta, GA 30912; Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, GA 30912;
authors.forename: Md Nasrul
authors.initials: MN
authors.lastname: Hoda
authors.affiliation: Department of Neurology, Henry Ford Health System, Detroit, MI 48202;
authors.forename: Mandar
authors.initials: M
authors.lastname: Deshpande
authors.affiliation: Department of Orthopedic Surgery, Institute of Regenerative and Reparative Medicine, Augusta University, Augusta, GA 30912;
authors.forename: Sadanand
authors.initials: S
authors.lastname: Fulzele
authors.affiliation: Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905;
authors.forename: Alexander
authors.initials: A
authors.lastname: Denic
authors.affiliation: Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905;
authors.forename: Viji
authors.initials: V
authors.lastname: Shridhar
authors.affiliation: Department of Anatomy and Cell Biology, School of Medicine, Wayne State University, Detroit, MI 48202;
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.affiliation: INSERM, U1016, Institut Cochin, Paris 75014, France; CNRS, UMR 8104, Paris 75014, France; and Université René Descartes, Sorbonne Paris Cité, Paris 75270, France.
authors.forename: Benoit
authors.identifier: 0000-0002-0121-0224
authors.initials: B
authors.lastname: Viollet
authors.affiliation: Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905;
authors.forename: Moses
authors.initials: M
authors.lastname: Rodriguez
authors.affiliation: Department of Neurology, Henry Ford Health System, Detroit, MI 48202; sgiri1@hfhs.org.
authors.forename: Shailendra
authors.identifier: 0000-0002-7123-829X
authors.initials: S
authors.lastname: Giri
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D015151:Immunoblotting; D020381:Interleukin-17 / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D058504:Th17 Cells / Q000276:immunology
chemical_list: D020381:Interleukin-17; D055372:AMP-Activated Protein Kinases