Targeting glycolysis in Th2 cells by pterostilbene attenuates clinical severities in an asthmatic mouse model and IL-4 production in peripheral blood from asthmatic patients

Asthma, a major non-communicable disease, affects both adults and children and is associated with high morbidity compared with other chronic diseases. The glycolysis-associated activation of type 2 helper T (Th2) cells is the critical immunopathological mechanism involved in asthma deterioration. Long-term use of steroids as a medical treatment for asthma induces side effects and resistance. Pterostilbene (PS), a stilbenoid compound found in blueberry and vines, exhibits antihyperglycemic and anti-inflammatory properties. Thus, we hypothesized that the modulation of T cell immunity by PS may be an applicable intervention to treat asthma. Airway hyperresponsiveness, interleukin (IL)-4 and IL-13 levels, IgE, IgG, pulmonary infiltrated monocytes and eosinophils, and mucosubstances were measured in house dust mite (HDM)-induced asthmatic mice under PS treatment. Bioenergetic metabolism, PI3K-mTOR signalling, GATA3 expression and histone acetylation in PS-treated Th2 cells were investigated. PS improved HDM-induced pulmonary allergic airway inflammation by inhibiting Th2 cell and eosinophil accumulation in HDM asthmatic mice both in the preventive and therapeutic models. Targeting glycolysis resulted in IL-4 inhibition via the downregulation of mTOR, GATA3 and histone acetylation in PS-treated Th2 cells. Glucose supplementation reversed the inhibitory effect of PS on Th2 cells in vitro. Adoptive transfer with glucose-treated Th2 cells enhanced Th2 activation and eosinophilic accumulation in PS-treated asthmatic mice. Furthermore, PS significantly inhibited IL-4 production of CD4⁺ T cells from the peripheral blood mononuclear cells of patients with asthma. PS attenuates HDM-induced asthma via the inhibition of the Glut1/mTOR/GATA3 axis in Th2 cells, which supports the potential pharmaceutical application of PS treatment for asthma.