Modulation of PKM Activity Affects the Differentiation of T17 Cells

Overview

Journal Sci Signal

Specialties Cell Biology
Physiology
Science

Date 2020 Oct 28

PMID 33109748

Citations 14

Authors

Scott M Seki

Kacper Posyniak

Rebecca McCloud

Dorian A Rosen

Anthony Fernandez-Castaneda

Rebecca M Beiter

Vlad Serbulea

Sarah C Nanziri

Nikolas Hayes

Charles Spivey

Lelisa Gemta

Timothy N J Bullock

Ku-Lung Hsu

Alban Gaultier

Affiliations

Soon will be listed here.

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). T17 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 T17 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 T17 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.

Citing Articles

T cell metabolism in kidney immune homeostasis.

Liu Z, Dai B, Bao J, Pan Y Front Immunol. 2024; 15:1498808.

PMID: 39737193 PMC: 11684269. DOI: 10.3389/fimmu.2024.1498808.

Targeting pyruvate kinase M2 for the treatment of kidney disease.

Chen D, Han J, Liu H, Feng K, Li P Front Pharmacol. 2024; 15:1376252.

PMID: 38910890 PMC: 11190346. DOI: 10.3389/fphar.2024.1376252.

Emerging roles of lactate in acute and chronic inflammation.

Fang Y, Li Z, Yang L, Li W, Wang Y, Kong Z Cell Commun Signal. 2024; 22(1):276.

PMID: 38755659 PMC: 11097486. DOI: 10.1186/s12964-024-01624-8.

Imbalance in Glucose Metabolism Regulates the Transition of Microglia from Homeostasis to Disease-Associated Microglia Stage 1.

Liu Y, Kwok W, Yoon H, Ryu J, Stevens P, Hawkinson T J Neurosci. 2024; 44(20).

PMID: 38565291 PMC: 11097271. DOI: 10.1523/JNEUROSCI.1563-23.2024.

Identification of protein-protein interaction bridges for multiple sclerosis.

Yazici G, Kurt Vatandaslar B, Aydin Canturk I, Aydinli F, Arici Duz O, Karakoc E Bioinformatics. 2023; 39(4).

PMID: 37018152 PMC: 10115466. DOI: 10.1093/bioinformatics/btad175.

References

Cruz-Orengo L, Holman D, Dorsey D, Zhou L, Zhang P, Wright M . CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity. J Exp Med. 2011; 208(2):327-39. PMC: 3039853. DOI: 10.1084/jem.20102010. View

Wessel D, Flugge U . A method for the quantitative recovery of protein in dilute solution in the presence of detergents and lipids. Anal Biochem. 1984; 138(1):141-3. DOI: 10.1016/0003-2697(84)90782-6. View

Anastasiou D, Yu Y, Israelsen W, Jiang J, Boxer M, Hong B . Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol. 2012; 8(10):839-47. PMC: 3711671. DOI: 10.1038/nchembio.1060. View

MacIver N, Jacobs S, Wieman H, Wofford J, Coloff J, Rathmell J . Glucose metabolism in lymphocytes is a regulated process with significant effects on immune cell function and survival. J Leukoc Biol. 2008; 84(4):949-57. PMC: 2638731. DOI: 10.1189/jlb.0108024. View

Peters A, Pitcher L, Sullivan J, Mitsdoerffer M, Acton S, Franz B . Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity. 2011; 35(6):986-96. PMC: 3422678. DOI: 10.1016/j.immuni.2011.10.015. View

Ohkura N, Kitagawa Y, Sakaguchi S . Development and maintenance of regulatory T cells. Immunity. 2013; 38(3):414-23. DOI: 10.1016/j.immuni.2013.03.002. View

Michalek R, Gerriets V, Jacobs S, Macintyre A, MacIver N, Mason E . Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol. 2011; 186(6):3299-303. PMC: 3198034. DOI: 10.4049/jimmunol.1003613. View

Jiang J, Boxer M, Vander Heiden M, Shen M, Skoumbourdis A, Southall N . Evaluation of thieno[3,2-b]pyrrole[3,2-d]pyridazinones as activators of the tumor cell specific M2 isoform of pyruvate kinase. Bioorg Med Chem Lett. 2010; 20(11):3387-93. PMC: 2874658. DOI: 10.1016/j.bmcl.2010.04.015. View

Seki S, Stevenson M, Rosen A, Arandjelovic S, Gemta L, Bullock T . Lineage-Specific Metabolic Properties and Vulnerabilities of T Cells in the Demyelinating Central Nervous System. J Immunol. 2017; 198(12):4607-4617. PMC: 5485845. DOI: 10.4049/jimmunol.1600825. View

10.

Dayton T, Jacks T, Vander Heiden M . PKM2, cancer metabolism, and the road ahead. EMBO Rep. 2016; 17(12):1721-1730. PMC: 5283597. DOI: 10.15252/embr.201643300. View

11.

Bettelli E, Carrier Y, Gao W, Korn T, Strom T, Oukka M . Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006; 441(7090):235-8. DOI: 10.1038/nature04753. View

12.

Dang E, Barbi J, Yang H, Jinasena D, Yu H, Zheng Y . Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. 2011; 146(5):772-84. PMC: 3387678. DOI: 10.1016/j.cell.2011.07.033. View

13.

Almeida L, Lochner M, Berod L, Sparwasser T . Metabolic pathways in T cell activation and lineage differentiation. Semin Immunol. 2016; 28(5):514-524. DOI: 10.1016/j.smim.2016.10.009. View

14.

Takatori H, Kawashima H, Suzuki K, Nakajima H . Role of p53 in systemic autoimmune diseases. Crit Rev Immunol. 2015; 34(6):509-16. DOI: 10.1615/critrevimmunol.2014012193. View

15.

Cocolakis E, Dai M, Drevet L, Ho J, Haines E, Ali S . Smad signaling antagonizes STAT5-mediated gene transcription and mammary epithelial cell differentiation. J Biol Chem. 2007; 283(3):1293-1307. DOI: 10.1074/jbc.M707492200. View

16.

Croxford A, Lanzinger M, Hartmann F, Schreiner B, Mair F, Pelczar P . The Cytokine GM-CSF Drives the Inflammatory Signature of CCR2+ Monocytes and Licenses Autoimmunity. Immunity. 2015; 43(3):502-14. DOI: 10.1016/j.immuni.2015.08.010. View

17.

Meng X, Nikolic-Paterson D, Lan H . TGF-β: the master regulator of fibrosis. Nat Rev Nephrol. 2016; 12(6):325-38. DOI: 10.1038/nrneph.2016.48. View

18.

Yang X, Panopoulos A, Nurieva R, Chang S, Wang D, Watowich S . STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem. 2007; 282(13):9358-9363. DOI: 10.1074/jbc.C600321200. View

19.

Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M . Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation. Nat Med. 2007; 13(10):1173-5. PMC: 5114125. DOI: 10.1038/nm1651. View

20.

Hu X, Wang Y, Hao L, Liu X, Lesch C, Sanchez B . Sterol metabolism controls T(H)17 differentiation by generating endogenous RORγ agonists. Nat Chem Biol. 2015; 11(2):141-7. DOI: 10.1038/nchembio.1714. View