Alpha-methylacyl-CoA racemase deletion has mutually counteracting effects on T-cell responses, associated with
Nadja Tafferner1, Julia Barthelmes2, Max Eberle2
1Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology (TMP), Frankfurt am Main, Germany.
Abstract:
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Altering the metabolism of immune cells is an attractive strategy to modify their activity during autoimmunity in MS. We investigated the effect of modulating fatty acid metabolism in an animal model of MS, EAE. Alpha-methylacyl-CoA racemase (AMACR) converts R-configuration branched fatty acids into the S-configuration, thereby preparing them for β-oxidation. We observed a significant, disease-dependent elevation of AMACR expression in monocytes and T cells from blood, draining lymph nodes and spleen of EAE mice during the preclinical phase. In vitro analysis revealed that the proliferation of T cells was inhibited in AMACR KO mice, but T-cell polarization was switched toward a pathogenic state involving the production of more IFN-γ and IL-17, but less IL-4. These opposing effects appeared to cancel out each other in vivo, because AMACR KO EAE mice showed a marginal increase in the severity of early clinical symptoms. AMACR was not regulated in the white blood cells of MS patients. Our data show that AMACR is regulated in immune cells during EAE, but it is not a suitable target for the treatment of MS due to its opposing effects.
Insights
Alpha-methylacyl-CoA racemase (AMACR) is upregulated in immune cells during experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS). However, AMACR is not a viable therapeutic target for MS due to opposing effects on T cells.
Area of Science:
- Neuroimmunology
- Immunometabolism
- Central Nervous System Disorders
Background:
- Multiple sclerosis (MS) involves immune cell-mediated inflammation and demyelination in the central nervous system.
- Modulating immune cell metabolism presents a potential therapeutic strategy for autoimmune diseases like MS.
- Fatty acid metabolism, specifically the role of Alpha-methylacyl-CoA racemase (AMACR), is explored in the context of MS.
Purpose of the Study:
- To investigate the role of AMACR in immune cell metabolism during experimental autoimmune encephalomyelitis (EAE), an animal model for MS.
- To determine if AMACR is a potential therapeutic target for MS treatment.
Main Methods:
- Utilized an EAE mouse model to study AMACR expression in immune cells (monocytes, T cells) during disease progression.
- Performed in vitro analysis of T cell proliferation and polarization in AMACR knockout (KO) mice.
- Assessed AMACR regulation in white blood cells from human MS patients.
Main Results:
- AMACR expression was significantly elevated in monocytes and T cells from EAE mice during the preclinical phase.
- In vitro, AMACR KO T cells showed inhibited proliferation but skewed towards a pathogenic phenotype (increased IFN-γ, IL-17; decreased IL-4).
- AMACR KO EAE mice exhibited only a marginal increase in early clinical symptom severity, and AMACR was not regulated in MS patient immune cells.
Conclusions:
- AMACR is dynamically regulated in immune cells during EAE, suggesting a role in the disease process.
- Despite its regulation in EAE, AMACR's opposing effects on T cell function make it unsuitable as a therapeutic target for MS.
- Further research into immunometabolism in MS may identify more promising therapeutic avenues.
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