Introdunction: Neutrophilic airway inflammation is insensitive to steroids and is thereby considered as a substantial clinical problem. Th17 cells represent a distinct population of CD4+ T cells that mediate neutrophilic inflammation. On the other hand, regulatory T(Treg) cells are able to suppress airway inflammation. Recent advances in the field of immunometabolism support the concept that Th1, Th2, and Th17 cells utilize large amounts of glucose and exhibits increased aerobic glycolysis to meet their energetic and anabolic demands, whereas Treg cells primarily use fatty acid oxidation. Pyruvate dehydrogenase kinases(PDKs) are gate-keeping enzymes for regulating aerobic glycolysis and inhibition of PDKs can suppress the metabolic process. In this study, we aimed to investigate the effect of dichloroaceate(DCA), a known PDK inhibitor, on neutrophilic airway inflammation in a mouse model of neutrophilic asthma.
Methods and Results: Histological staining in lung sections showed that treatment with DCA ameliorates inflammatory cell infiltration into lung tissue and goblet cell hyperplasia in a mouse model of neutrophilic asthma. Bronchoalveolar lavage cells from DCA-treated mice showed less infiltration of total inflammatory cells and lower neutrophil and eosinophil counts compared with those in control mice. In addition, treatment with DCA significantly decreased mRNA expression of IL-4 and IL-17A in lung tissues of mice with neutrophilic asthma, whereas IFN-gamma expression was not changed. IL-10 expression was slightly increased by DCA treatment, although there was no statistical significance. Moreover, flow cytometric analysis on lung-draining lymph nodes showed that treatment with DCA significantly decreased Th2 and Th17 populations and increased Treg population, whereas Th1 population was not affected.
Conclusion: Taken together, these findings suggest that treatment with DCA ameliorates neutrophilic airway inflammation through suppressing Th17 population and inducing Treg population. Our data provide the concept that DCA may be a promising therapeutic agent for neutrophilic asthma.