Aerobic glycolysis, a metabolic pathway essential for effector T cell survival and proliferation, regulates the differentiation of autoimmune T helper (Th) 17 cells. A recent study published in Cell Reports has reported that phosphoenolpyruvate (PEP), a glycolytic intermediate metabolite, suppresses the development of rheumatoid arthritis and multiple sclerosis by inhibiting T helper 17 (Th17) cells. This research could pave way for developing a novel therapeutic option to treat autoimmune diseases.
Dr. Huang and colleagues have shown that the supplementation of PEP inhibits the downstream glycolytic enzymes and increases the intracellular PEP levels as well as reduces the expression of interleukin-17A. The binding of PEP to JunB prevents DNA binding of the JunB/basic leucine zipper transcription factor ATF-like (BATF)/interferon regulatory factor 4 (IRF4) complex, thereby regulating the Th17 transcriptional program. The researchers noted that the daily administration of PEP to mice models hindered the production of Th17 cells and improved Th17-related autoimmune encephalomyelitis, indicating the potential use of PEP as a therapeutic agent for autoimmune diseases.
A 2020 study conducted by Damasceno and coworkers reported another enzyme, pyruvate kinase M2 (PKM2), as a critical nonmetabolic regulator that modifies the differentiation and function of Th17 cells in autoimmune-mediated inflammation. The experts found that pyruvate kinase M2 is expressed in vitro throughout the differentiation of Th17 cells. This enzyme translocates into the nucleus and interacts with the signal transducer and activator of transcription 3 to enhance activation, resulting in Th17 cell differentiation. They found that deletion of T cell-specific pyruvate kinase M2 has impaired Th17 cell differentiation contributing to the improvement of symptoms of autoimmune-mediated inflammation.
Though the results of these studies showed the clinical potential of PEP and pyruvate kinase M2, extensive studies on assessing their efficiency are warranted. Future studies should focus on developing newer biologics with a thorough understanding of the molecular basis of autoimmune diseases.
- Huang TY, Hirota M, Sasaki D, Kalra RS, Chien HC, Tamai M, et al. Phosphoenolpyruvate regulates the Th17 transcriptional program and inhibits autoimmunity. Cell Reports. 2023 Mar 28;42(3).
- Damasceno LE, Prado DS, Veras FP, Fonseca MM, Toller-Kawahisa JE, Rosa MH, et al. PKM2 promotes Th17 cell differentiation and autoimmune inflammation by fine-tuning STAT3 activation. Journal of Experimental Medicine. 2020 Oct 5;217(10).