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

Ashutosh K Mangalam; Ramandeep Rattan; Hamid Suhail; Jaspreet Singh; Md Nasrul Hoda; Mandar Deshpande; Sadanand Fulzele; Alexander Denic; Viji Shridhar; Ashok Kumar; Benoit Viollet; Moses Rodriguez; Shailendra Giri

doi:10.4049/jimmunol.1501549

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

Journal article

Peer reviewed

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

Ashutosh K Mangalam, Ramandeep Rattan, Hamid Suhail, Jaspreet Singh, Md Nasrul Hoda, Mandar Deshpande, Sadanand Fulzele, Alexander Denic, Viji Shridhar, Ashok Kumar, …

Journal of immunology (Baltimore, Md. : 1950), Vol.197(3), pp.747-760

08/01/2016

DOI: 10.4049/jimmunol.1501549

PMID: 27354217

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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.

Flow Cytometry

Polymerase Chain Reaction

AMP-Activated Protein Kinases - metabolism

Encephalomyelitis, Autoimmune, Experimental - pathology

Encephalomyelitis, Autoimmune, Experimental - metabolism

Interleukin-17 - immunology

Encephalomyelitis, Autoimmune, Experimental - immunology

Immunoblotting

Adoptive Transfer

Mice, Knockout

CD4-Positive T-Lymphocytes - immunology

Animals

Th17 Cells - immunology

Mice

Macrophages - immunology

Details

Title: Subtitle: AMP-Activated Protein Kinase Suppresses Autoimmune Central Nervous System Disease by Regulating M1-Type Macrophage-Th17 Axis
Creators: Ashutosh K Mangalam - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242
Ramandeep Rattan - Division of Gynecologic Oncology, Department of Women's Health Services, Henry Ford Health System, Detroit, MI 48202
Hamid Suhail - Henry Ford Health System
Jaspreet Singh - Henry Ford Health System
Md Nasrul Hoda - Augusta University
Mandar Deshpande - Henry Ford Health System
Sadanand Fulzele - Augusta University
Alexander Denic - Mayo Clinic
Viji Shridhar - Mayo Clinic
Ashok Kumar - Department of Anatomy and Cell Biology, School of Medicine, Wayne State University, Detroit, MI 48202
Benoit Viollet - Institut Cochin
Moses Rodriguez - Mayo Clinic
Shailendra Giri - Department of Neurology, Henry Ford Health System, Detroit, MI 48202; sgiri1@hfhs.org
Resource Type: Journal article
Publication Details: Journal of immunology (Baltimore, Md. : 1950), Vol.197(3), pp.747-760
DOI: 10.4049/jimmunol.1501549
PMID: 27354217
NLM abbreviation: J Immunol
ISSN: 0022-1767
eISSN: 1550-6606
Publisher: American Association of Immunologists; United States
Language: English
Date published: 08/01/2016
Academic Unit: Pathology; Iowa Neuroscience Institute
Record Identifier: 9983905638702771

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