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 T Fulzele, Alexander Denic, Viji Shridhar, Ashok Kumar, Benoit Viollet, Moses Rodriguez, Shailendra Giri

Research output: Contribution to journalArticle

14 Citations (Scopus)

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. AMPKa1 knockout (a1KO) 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-1b, impaired blood-brain barrier integrity, and increased infiltration of inflammatory cells in the CNS. Infiltrated CD4 cells in the brains and spinal cords of a1KO 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 a1KO mice was due to polarization of macrophages (Mf) to proinflammatory M1 type phenotype (IL-10lowIL-23/IL-1b/IL-6high), and these M1 Mf showed stronger capacity to induce allogenic as well as Ag-specific (myelin oligodendrocyte glycoprotein [MOG]35-55) T cell response. Mf from a1KO 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-1b/IL-23-mediated induction of IL-6 production in a1KOMf, 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.

Original languageEnglish (US)
Pages (from-to)747-760
Number of pages14
JournalJournal of Immunology
Volume197
Issue number3
DOIs
StatePublished - Aug 1 2016

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Autoimmune Diseases of the Nervous System
AMP-Activated Protein Kinases
Central Nervous System Diseases
Autoimmune Experimental Encephalomyelitis
Interleukin-17
Interleukin-23
Macrophages
Knockout Mice
Granulocyte-Macrophage Colony-Stimulating Factor
T-Lymphocytes
Spinal Cord
Myelin-Oligodendrocyte Glycoprotein
Phenotype
Demyelinating Diseases
Encephalitis
Blood-Brain Barrier
Autoimmune Diseases
Multiple Sclerosis
Interleukin-6
Animal Models

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

AMP-activated protein kinase suppresses autoimmune central nervous system disease by regulating M1-type macrophage-Th17 axis. / Mangalam, Ashutosh K.; Rattan, Ramandeep; Suhail, Hamid; Singh, Jaspreet; Hoda, MD Nasrul; Deshpande, Mandar; Fulzele, Sadanand T; Denic, Alexander; Shridhar, Viji; Kumar, Ashok; Viollet, Benoit; Rodriguez, Moses; Giri, Shailendra.

In: Journal of Immunology, Vol. 197, No. 3, 01.08.2016, p. 747-760.

Research output: Contribution to journalArticle

Mangalam, AK, Rattan, R, Suhail, H, Singh, J, Hoda, MDN, Deshpande, M, Fulzele, ST, Denic, A, Shridhar, V, Kumar, A, Viollet, B, Rodriguez, M & Giri, S 2016, 'AMP-activated protein kinase suppresses autoimmune central nervous system disease by regulating M1-type macrophage-Th17 axis', Journal of Immunology, vol. 197, no. 3, pp. 747-760. https://doi.org/10.4049/jimmunol.1501549
Mangalam, Ashutosh K. ; Rattan, Ramandeep ; Suhail, Hamid ; Singh, Jaspreet ; Hoda, MD Nasrul ; Deshpande, Mandar ; Fulzele, Sadanand T ; Denic, Alexander ; Shridhar, Viji ; Kumar, Ashok ; Viollet, Benoit ; Rodriguez, Moses ; Giri, Shailendra. / AMP-activated protein kinase suppresses autoimmune central nervous system disease by regulating M1-type macrophage-Th17 axis. In: Journal of Immunology. 2016 ; Vol. 197, No. 3. pp. 747-760.
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