Background: Mycobacterium tuberculosis (Mtb), causes extensive lung tissue remodelling, driven by matrix metalloproteinases (MMPs) secreted by fibroblasts. Metabolic pathways may regulate inflammatory responses to Tuberculosis (TB). The aim of this study is to investigate whether glycolysis modulates fibroblast-dependent lung remodelling in TB.

Methods: Primary human lung fibroblasts (PHLF) were stimulated with conditioned media from control (CoMCon) or Mtb-infected monocytes (CoMTb) for 24-72 h. MMP and TIMP secretion and gene expression were measured by ELISA and qRT-PCR.

Results: Stimulation of PHLF with CoMTb induced significantly elevated MMP1 (a key collagenase) secretion and gene expression compared to CoMCon (522.2±47.5 vs 200.9±19.2 ng/ml respectively, p=0.0001), with maximal secretion observed at 72 h. Similarly, secretion of MMP3 (which activates MMP1) from PHLF was also significantly upregulated compared to CoMCon stimulation (1280.7±52.4 vs 80.1±11.3 ng/ml respectively, p<0.0001). Inhibiting glycolysis with 1 mM 2-Deoxy-D-glucose (2DG) resulted in a dose dependent reduction in CoMTb-induced MMP1 secretion and gene expression in PHLF, which was observed from 24 h post stimulation (44.8±7.2 vs 74.4±9.6 ng/ml, respectively p=0.0003 and 67.3±18.5 vs 189.3±21.4 respectively, p=0.0001). A reduction in timp1 gene expression from 2DG-treated PHLF stimulated with CoMTb was also observed at 24 h (0.34±0.12 vs 11.8±3.2, p=0.0035).

Conclusion: Monocyte-dependent networks drive MMP and TIMP secretion from fibroblasts in TB which are downregulated upon inhibition of glycolysis. Host-directed therapies targeting metabolic pathways may decrease lung fibrosis in TB.