Background: Tuberculosis (TB), the deadliest infection worldwide, causes severe tissue destruction associated with excess inflammation. This process is driven by matrix metalloproteinase (MMP) enzymes regulated by the innate immune response. Patients also experience profound metabolic changes, such as weight loss. TB-infected macrophages show the Warburg effect, a metabolic shift from oxidative phosphorylation to aerobic glycolysis. However, the relationship between innate inflammation and cellular metabolism in TB is unclear.
Materials/methods: Primary monocyte-derived macrophages (MDMs) or normal human bronchial epithelial cells (NHBEs) were incubated with specific metabolic inhibitors or transfected with siRNA. Glycolysis was blocked with the hexokinase (HK) inhibitor, 2-deoxyglucose (2DG). Cells were then directly infected with live, virulent Mycobacterium tuberculosis (M.tb) H37Rv or stimulated with TB cytokine networks. Protein secretion and expression, gene expression and functional tissue damage were measured by ELISA, luminex, zymography, Western blot, real-time PCR and DQ collagen assay. HK2 immunohistochemistry was performed in samples from a murine TB model and TB patients.
Results: HK2 was highly expressed in murine and human tissue sites of TB inflammation. In vitro, 2DG downregulated gene expression and secretion of MMP-1 and the proinflammatory cytokine IL-1b; expression of the hypoxic transcription factor HIF-1a; functional matrix degradation and intracellular bacillary growth. The metabolic regulator AMPK upregulated MMP-1 secretion in TB, while MMP-1 was downregulated by the Pi3-kinase-Akt-mTORC1 signal transduction pathway.
Conclusions: MMP-1, HIF-1a and pro-inflammatory cytokines are modulated by glycolysis, AMPK and the Pi3-kinase-Akt-mTORC1 pathway in TB. Immunometabolic regulation of tissue destruction in TB might provide new avenues for host-directed therapies.