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Updated: Mar 18, 2026
Determining Immune System Suppression versus CNS Protection for Pharmacological Interventions in Autoimmune Demyelination
Published on: September 12, 2016
AMP-Activated Protein Kinase Suppresses Autoimmune Central Nervous System Disease by Regulating M1-Type
Ashutosh K Mangalam1, Ramandeep Rattan2, Hamid Suhail3
1Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
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.
Insights
AMP-activated protein kinase (AMPK) regulates inflammation by controlling the M1 macrophage and Th17 cell axis. Loss of AMPK worsens experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis model, by increasing inflammatory cytokines.
Area of Science:
- Immunology
- Neuroscience
- Metabolic signaling
Background:
- AMP-activated protein kinase (AMPK) is a key metabolic regulator.
- AMPK's role in inflammation, particularly in neuroinflammatory diseases like experimental autoimmune encephalomyelitis (EAE), is not fully understood.
- Previous studies indicated that loss of AMPK exacerbates EAE severity.
Purpose of the Study:
- To elucidate the precise mechanisms by which AMPK influences inflammatory responses in EAE.
- To investigate the impact of AMPKα1 knockout on immune cell polarization and cytokine production in the context of EAE.
Main Methods:
- Utilized AMPKα1 knockout (α1KO) mice and wild-type littermates subjected to EAE induction.
- Analyzed demyelination, inflammation, blood-brain barrier integrity, and inflammatory cell infiltration in the central nervous system (CNS).
- Assessed cytokine profiles (IL-17, IL-23, IL-1β, IL-6, GM-CSF) and macrophage (Mϕ) polarization (M1 phenotype).
- Evaluated T cell responses, including encephalitogenic potential of myelin oligodendrocyte glycoprotein (MOG)-specific CD4 T cells.
Main Results:
- α1KO mice with EAE exhibited severe demyelination and CNS inflammation compared to wild-type.
- Higher expression of pro-inflammatory Th17 cytokines (IL-17, IL-23, IL-1β) and increased inflammatory cell infiltration were observed in α1KO mice.
- Infiltrated CD4 cells in α1KO mice were predominantly IL-17 and GM-CSF double-positive.
- Macrophages in α1KO mice polarized to a pro-inflammatory M1 phenotype, enhancing T cell responses.
- AMPK deficiency led to IL-1β/IL-23-mediated IL-6 production in Mϕ, promoting Th17 cell differentiation.
Conclusions:
- AMPK plays a critical role in controlling neuroinflammation by regulating the M1 macrophage-Th17 cell axis.
- Loss of AMPKα1 exacerbates EAE through enhanced M1 polarization and Th17 cytokine production.
- Targeting AMPK may offer a therapeutic strategy for managing inflammatory diseases like multiple sclerosis.
