Research ArticleImmunology

Modulation of PKM activity affects the differentiation of TH17 cells

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Science Signaling  27 Oct 2020:
Vol. 13, Issue 655, eaay9217
DOI: 10.1126/scisignal.aay9217

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Rethinking metabolic manipulations in MS

The metabolic state of TH17 cells determines whether they drive experimental autoimmune encephalitis (EAE), a mouse model of multiple sclerosis (MS). Activation of the metabolic enzyme PKM2, which catalyzes a critical step in glycolysis, has been proposed as a potential treatment for MS. Seki et al. found that although PKM2 activators did limit TH17 cell differentiation by suppressing the production of IL-17, they enhanced the production of the encephalitogenic cytokine GM-CSF, which was associated with disease pathology in the brain rather than the spinal cord. PKM2 activators also blocked the generation of Tregs, an anti-inflammatory T cell subset that suppresses T cell activation. Genetic ablation of Pkm2 led to a compensatory increase in the related enzyme PKM1, which suggests that inhibiting PKM2 may lead to similar outcomes as activating PKM2. These results suggest that the therapeutic potential of PKM2 activators for MS must be reassessed.

Abstract

Small molecules that promote the metabolic activity of the pyruvate kinase isoform PKM2, such as TEPP-46 and DASA-58, limit tumorigenesis and inflammation. To understand how these compounds alter T cell function, we assessed their therapeutic activity in a mouse model of T cell–mediated autoimmunity that mimics multiple sclerosis (MS). TH17 cells are believed to orchestrate MS pathology, in part, through the production of two proinflammatory cytokines: interleukin-17 (IL-17) and GM-CSF. We found that both TEPP-46 and DASA-58 suppressed the development of IL-17–producing TH17 cells but increased the generation of those producing GM-CSF. This switch redirected disease pathology from the spinal cord to the brain. In addition, we found that activation of PKM2 interfered with TGF-β1 signaling, which is necessary for the development of TH17 and regulatory T cells. Collectively, our data clarify the therapeutic potential of PKM2 activators in MS-like disease and how these agents alter T cell function.

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