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J Immunol. 2016 Aug 1;197(3):747-60. doi: 10.4049/jimmunol.1501549. Epub 2016 Jun 27.

AMP-Activated Protein Kinase Suppresses Autoimmune Central Nervous System Disease by Regulating M1-Type Macrophage-Th17 Axis.

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Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
Division of Gynecologic Oncology, Department of Women's Health Services, Henry Ford Health System, Detroit, MI 48202;
Department of Neurology, Henry Ford Health System, Detroit, MI 48202;
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;
Department of Orthopedic Surgery, Institute of Regenerative and Reparative Medicine, Augusta University, Augusta, GA 30912;
Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905;
Department of Experimental Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905;
Department of Anatomy and Cell Biology, School of Medicine, Wayne State University, Detroit, MI 48202;
INSERM, U1016, Institut Cochin, Paris 75014, France; CNRS, UMR 8104, Paris 75014, France; and Université René Descartes, Sorbonne Paris Cité, Paris 75270, France.
Department of Neurology, Henry Ford Health System, Detroit, MI 48202;


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.

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