Signaling metabolite L-2-hydroxyglutarate activates the transcription factor HIF-1α in lipopolysaccharide-activated macrophages

Activated macrophages undergo metabolic reprogram-ming, which not only supports their energetic demands but also allows for the production of specific metabolites that function as signaling molecules. Several Krebs cycles, or Krebs-cycle-derived metabolites, including succinate, alpha- ketoglutarate, and itaconate, have recently been shown to modulate macrophage function. The accumulation of 2-hydroxyglutarate (2HG) has also been well documented in transformed cells and more recently shown to play a role in T cell and dendritic cell function. Here we have found that the abundance of both enantiomers of 2HG is increased in LPS-activated macrophages. We show that L-2HG, but not D-2HG, can promote the expression of the proinflammatory cytokine IL-1 beta and the adoption of an inflammatory, highly glycolytic metabolic state. These changes are likely mediated through activation of the transcription factor hypoxia-inducible factor-1 alpha (HIF-1 alpha) by L-2HG, a known inhibitor of the HIF prolyl hydroxylases. Expression of the enzyme responsible for L-2HG degradation, L-2HG dehydrogenase (L-2HGDH), was also found to be decreased in LPS-stimulated macrophages and may therefore also contribute to L-2HG accumulation. Finally, overexpression of L-2HGDH in HEK293 TLR4/MD2/CD14 cells inhibited HIF-1 alpha activa-tion by LPS, while knockdown of L-2HGDH in macrophages boosted the induction of HIF-1 alpha-dependent genes, as well as increasing LPS-induced HIF-1 alpha activity. Taken together, this study therefore identifies L-2HG as a metabolite that can regulate HIF-1 alpha in macrophages.

Automated summary

Activated macrophages undergo metabolic reprogramming, in which the metabolites such as 2HG play a role in regulating their function. In LPS-activated macrophages, both enantiomers of 2HG, L-2HG and D-2HG, are accumulated. L-2HG can promote the expression of IL-1 beta and induce an inflammatory metabolic state. These changes may be mediated through activation of HIF-1 alpha by L-2HG, and decreased expression of L-2HGDH may contribute to L-2HG accumulation.