title: The AMP analog AICAR modulates the Treg/Th17 axis through enhancement of fatty acid oxidation.
abstract: T cells must tightly regulate their metabolic processes to cope with varying bioenergetic demands depending on their state of differentiation. The metabolic sensor AMPK is activated in states of low energy supply and modulates cellular metabolism toward a catabolic state. Although this enzyme is known to be particularly active in regulatory T (Treg) cells, its impact on T helper (Th)-cell differentiation is poorly understood. We investigated the impact of several AMPK activators on Treg-cell differentiation and found that the direct activator AICAR (5-aminoimidazole-4-carboxamide ribonucleotide), but not the indirect activators metformin and 2-deoxyglucose, strongly enhanced Treg-cell induction by specifically enhancing Treg-cell expansion. Conversely, Th17 generation was impaired by the agent. Further investigation of the metabolic background of our observations revealed that AICAR enhanced both cellular mitochondrogenesis and fatty acid uptake. Consistently, increased Treginduction was entirely reversible on inhibition of fatty acid oxidation, thus confirming the dependence of AICAR's effects on metabolic pathways alterations. Translating our findings to an in vivo model, we found that the substance enhanced Tregcell generation on IL-2 complex-induced immune stimulation. We provide a previously unrecognized insight into the delicate interplay between immune cell function and metabolism and delineate a potential novel strategy for metabolism-targeting immunotherapy.-Gualdoni, G. A., Mayer, K. A., Göschl, L., Boucheron, N., Ellmeier, W., Zlabinger, G. J. The AMP analog AICAR modulates the Treg/Th17 axis through enhancement of fatty acid oxidation.
authors: Institute of Immunology, Center of Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Austria; and.
authors: Guido A
authors: GA
authors: Gualdoni
authors: Institute of Immunology, Center of Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Austria; and.
authors: Katharina A
authors: KA
authors: Mayer
authors: Institute of Immunology, Center of Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Austria; and.|Division of Rheumatology, Department of Internal Medicine 3, Medical University of Vienna, Austria.
authors: Lisa
authors: L
authors: Göschl
authors: Institute of Immunology, Center of Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Austria; and.
authors: Nicole
authors: N
authors: Boucheron
authors: Institute of Immunology, Center of Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Austria; and.
authors: Wilfried
authors: W
authors: Ellmeier
authors: Institute of Immunology, Center of Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Austria; and gerhard.zlabinger@meduniwien.ac.at.
authors: Gerhard J
authors: GJ
authors: Zlabinger
mesh_terms: D000249:Adenosine Monophosphate / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology; D010084:Oxidation-Reduction; D012265:Ribonucleotides / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects* / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D007004:Hypoglycemic Agents; D007376:Interleukin-2; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000249:Adenosine Monophosphate; D008687:Metformin; C031143:AICA ribonucleotide
keywords: AMPK; T cell; Th cell differentiation; immunometabolism; regulatory T cell