ATP citrate lyase (ACLY)-dependent immunometabolism in mucosal T cells drives experimental colitis in vivo.

OBJECTIVE: Mucosal T cells play a major role in inflammatory bowel disease (IBD). However, their immunometabolism during intestinal inflammation is poorly understood. Due to its impact on cellular metabolism and proinflammatory immune cell function, we here focus on the enzyme ATP citrate lyase (ACLY) in mucosal T cell immunometabolism and its relevance for IBD. DESIGN: ACLY expression and its immunometabolic impact on colitogenic T cell function were analysed in mucosal T cells from patients with IBD and in two experimental colitis models. RESULTS: ACLY was markedly expressed in colon tissue under steady-state conditions but was significantly downregulated in lamina propria mononuclear cells in experimental dextran sodium sulfate-induced colitis and in CD4+ and to a lesser extent in CD8+ T cells infiltrating the inflamed gut in patients with IBD. ACLY-deficient CD4+ T cells showed an impaired capacity to induce intestinal inflammation in a transfer colitis model as compared with wild-type T cells. Assessment of T cell immunometabolism revealed that ACLY deficiency dampened the production of IBD-relevant cytokines and impaired glycolytic ATP production but enriched metabolites involved in the biosynthesis of phospholipids and phosphatidylcholine. Interestingly, the short-chain fatty acid butyrate was identified as a potent suppressor of ACLY expression in T cells, while IL-36α and resolvin E1 induced ACLY levels. In a translational approach, in vivo administration of the butyrate prodrug tributyrin downregulated mucosal infiltration of ACLYhigh CD4+ T cells and ameliorated chronic colitis. CONCLUSION: ACLY controls mucosal T cell immunometabolism and experimental colitis. Therapeutic modulation of ACLY expression in T cells emerges as a novel strategy to promote the resolution of intestinal inflammation.

Memantine, an NMDA receptor antagonist, attenuates cardiac remodeling, lipid peroxidation and neutrophil recruitment in heart failure: A cardioprotective agent?

In addition to their role in the central nervous system (CNS), N-methyl-d-aspartate (NMDA) receptors activation contributes to myocardial pathogenesis. This study sought to determine the potential cardioprotective effects of pre-treatment with memantine, an NMDA receptor antagonist, in heart failure (HF). A subcutaneous injection of isoproterenol (5 mg/kg/day) for 14 days was used for the induction of heart failure in rats. Memantine was injected intraperitoneally (ip) at doses of 5 and 20 mg/kg one week before isoproterenol injection for 21 days (n = 8 each group). Then, hemodynamic, electrocardiogram and histopathological changes as well as lipid peroxidation, myeloperoxidase (MPO) and adenosine monophosphate-activated protein kinase (AMPK) activity were evaluated. Histopathological analysis showed a marked attenuation of myocyte necrosis and fibrosis in memantine 20 mg/kg pre-treated group (p < 0.001) in comparison to HF group. Pre-treatment with memantine 20 mg/kg significantly reduced myocardial edematous, MPO activity and malondialdehyde (MDA) levels in comparison to HF group (p < 0.05, p < 0.05 and p < 0.001 respectively). Memantine had no significant effect on hemodynamic parameters and AMPK activity but improved the electrocardiogram (ECG) pattern. Our results for the first time showed cardioprotective effects of memantine in HF through reduction in cardiac remodeling, lipid peroxidation and neutrophil infiltration. In addition these effects are through an AMPK-independent pathways.