Dichloroacetate alleviates development of collagen II-induced arthritis in female DBA/1 mice

Abstract

IntroductionDichloroacetate (DCA) has been in clinical use for the treatment of lactacidosis and inherited mitochondrial disorders. It has potent anti-tumor effects both in vivo and in vitro, facilitating apoptosis and inhibiting proliferation. The pro-apoptotic and anti-proliferative properties of DCA prompted us to investigate the effects of this compound in arthritis.MethodsIn the present study, we used DCA to treat murine collagen type II (CII)-induced arthritis (CIA), an experimental model of rheumatoid arthritis. DBA/1 mice were treated with DCA given in drinking water.ResultsMice treated with DCA displayed much slower onset of CIA and significantly lower severity (P < 0.0001) and much lower frequency (36% in DCA group vs. 86% in control group) of arthritis. Also, cartilage and joint destruction was significantly decreased following DCA treatment (P = 0.005). Moreover, DCA prevented arthritis-induced cortical bone mineral loss. This clinical picture was also reflected by lower levels of anti-CII antibodies in DCA-treated versus control mice, indicating that DCA affected the humoral response. In contrast, DCA had no effect on T cell- or granulocyte-mediated responses. The beneficial effect of DCA was present in female DBA/1 mice only. This was due in part to the effect of estrogen, since ovariectomized mice did not benefit from DCA treatment to the same extent as sham-operated controls (day 30, 38.7% of ovarectomized mice had arthritis vs. only 3.4% in sham-operated group).ConclusionOur results indicate that DCA delays the onset and alleviates the progression of CIA in an estrogen-dependent manner.

The Glucose Transporter Glut1 Is Selectively Essential for CD4 T Cell Activation and Effector Function

“…Mechanisms that control cell metabolism to support the specific functional needs of these cells have been described only recently (MacIver et al, 2013), but have proven promising (Bian et al, 2009; Eleftheriadis et al, 2013; Ostroukhova et al, 2012; Shi et al, 2011). To date, pharmacologic approaches have provided limited mechanistic insight, and the role of glucose uptake has been uncertain.…”

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.…”

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

“…In a previous study it was shown that DCA administration in lupus prone or normal mice enhances serum immunoglobulin levels (29), whereas another study has shown that in lupus prone mice DCA had no effect on the levels of anti-dsDNA IgG (9). On the other hand, in a murine model of collagen type II-induced arthritis, DCA alleviated arthritis only in female mice, in which it decreased anti-collagen type II antibodies without affecting the T cell response (30). In addition, although upon activation murine B-cells exhibit a balanced increase in lactate production and oxygen consumption, the induction of glycolysis is critical for B-cell proliferation and antibody production since DCA abrogated both of these processes (14).…”