Phosphoenolpyruvate (PEP) Treatment for Th17-Dependent Autoimmune Diseases (No. 0224)
Autoimmune diseases affect nearly 4% of the world’s population. T helper 17 (Th17) cells play a critical role in autoimmune diseases such as multiple sclerosis and psoriasis. Although Th17-related cytokines or transcription factors are attractive therapeutic targets to combat autoimmune responses, treatments often also attack helpful, gut-resident Th17 cells, compromising gut homeostasis and host defense. A team of OIST researchers led by Prof. Hiroki Ishikawa has developed a novel, broad-spectrum therapeutic approach to suppress Th17-dependent autoimmune responses. The team discovered that phosphoenolpyruvate (PEP) inhibits JunB-dependent Th17 generation. As JunB is required for generation of autoimmune Th17 cells but not for gut-resident Th17 cells, PEP selectively targets autoimmune Th17 cells without triggering intestinal side effects.
- Drug development
- Multiple sclerosis and other autoimmune diseases
- Selectively targets autoimmune Th17 cells without affecting gut Th17 cells
The researchers identified PEP, an intermediate metabolite of aerobic glycolysis, as a negative regulator of Th17 differentiation. Administering PEP was found to ameliorate Th17-dependent autoimmune encephalomyelitis in mice by inhibiting the expression of Th17 signature molecules, including IL-17A. PEP was found to bind to JunB, an AP-1 transcription factor that plays a key role in pathogenic Th17 differentiation, inhibiting DNA-binding of the JunB/BATF/IRF4 complex at the Il17a locus. PEP interacts with JunB proteins to mediate the interplay between aerobic glycolysis and Th17 differentiation, selectively targeting autoimmune cells.
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