The E3 ligase VHL controls alveolar macrophage function via metabolic-epigenetic regulation

Metabolic pathways such as glycolysis or oxidative phosphorylation play a key role in regulating macrophage function during inflammation and tissue repair. However, how exactly the VHL–HIF–glycolysis axis is involved in the function of tissue-resident macrophages remains unclear. Here we demonstrate that loss of VHL in myeloid cells resulted in attenuated pulmonary type 2 and fibrotic responses, accompanied by reduced eosinophil infiltration, decreased IL-5 and IL-13 concentrations, and ameliorated fiber deposition upon challenge. VHL deficiency uplifted glycolytic metabolism, decreased respiratory capacity, and reduced osteopontin expression in alveolar macrophages, which impaired the function of type 2 innate lymphoid cells but was significantly reversed by HIF1α inhibition or ablation. The up-regulated glycolysis altered the epigenetic modification of osteopontin gene, with the metabolic intermediate 3-phosphoglyceric acid as a key checkpoint controller. Thus, our results indicate that VHL acts as a crucial regulatory factor in lung inflammation and fibrosis by regulating alveolar macrophages.

Source: The Journal of Experimental Medicine - December 3, 2018 Category: Internal Medicine Authors: Zhang, W., Li, Q., Li, D., Li, J., Aki, D., Liu, Y.-C. Tags: Innate Immunity and Inflammation, Metabolism Articles Source Type: research