The role of low-level lactate production in airway inflammation in asthma

Abstract

Warburg and coworkers (Warburg O, Posener K, Negelein E. Z Biochem 152: 319, 1924) first reported that cancerous cells switch glucose metabolism from oxidative phosphorylation to aerobic glycolysis, and that this switch is important for their proliferation. Nothing is known about aerobic glycolysis in T cells from asthma. The objective was to study aerobic glycolysis in human asthma and the role of this metabolic pathway in airway hyperreactivity and inflammation in a mouse model of asthma. Human peripheral blood and mouse spleen CD4 T cells were isolated by negative selection. T cell proliferation was measured by thymidine incorporation. Cytokines and serum lactate were measured by ELISA. Mouse airway hyperreactivity to inhaled methacholine was measured by a FlexiVent apparatus. The serum lactate concentration was significantly elevated in clinically stable asthmatic subjects compared with healthy and chronic obstructive pulmonary disease controls, and negatively correlated with forced expiratory volume in 1 s. Proliferating CD4 T cells from human asthma and a mouse model of asthma produced higher amounts of lactate upon stimulation, suggesting a heightened glycolytic activity. Lactate stimulated and inhibited T cell proliferation at low and high concentrations, respectively. Dichloroacetate (DCA), an inhibitor of aerobic glycolysis, inhibited lactate production, proliferation of T cells, and production of IL-5, IL-17, and IFN-γ, but it stimulated production of IL-10 and induction of Foxp3. DCA also inhibited airway inflammation and hyperreactivity in a mouse model of asthma. We conclude that aerobic glycolysis is increased in asthma, which promotes T cell activation. Inhibition of aerobic glycolysis blocks T cell activation and development of asthma.

Comparison of the effect of the aerobic glycolysis inhibitor dichloroacetate and of the Krebs cycle inhibitor LW6 on cellular and humoral alloimmunity

“…This is in contrast with another study, which has shown that DCA inhibits T-cell clonal expansion (28). However, in that study T cells were murine, activated with anti-CD3/CD28 antibodies and the supra-pharmacological concentration of 20 mM DCA was used (28). We used MLRs, which is a model of alloimmunity (27), and DCA at a concentration of 1 mM, which is close to the blood concentrations of this drug when used for the treatment of hereditary lactic acidosis (19).…”

“…This is in contrast with another study, which has shown that DCA inhibits T-cell clonal expansion (28). However, in that study T cells were murine, activated with anti-CD3/CD28 antibodies and the supra-pharmacological concentration of 20 mM DCA was used (28).…”

Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation

“…DCA has also been shown to reduce proinflammatory cytokine production and promote FoxP3 expression in vitro and in several in vivo inflammatory models (19)(20)(21), although the mechanisms involved have not been established.…”

“…While DCA has been previously shown to suppress inflammation in arthritis, asthma, and alloreactivity (19)(20)(21), the specific effect on the differentiated CD4 + T cell subsets has not been examined in vivo. We therefore tested the ability of DCA to suppress the Th17-mediated inflammatory diseases.…”

“…DCA also can promote ROS in several cancer models that may drive cancer cell senescence (15,38,42). In the immune system, treatment of human peripheral blood mononuclear cells (PBMCs) with DCA inhibited proinflammatory cytokine production and promoted FoxP3 expression in the setting of asthma and alloreactivity (19)(20)(21). However, these studies did not directly examine the role of PDHK or DCA in T cell subsets or establish a mechanism of action.…”