Abstract
In pulmonary tuberculosis (TB), the inflammatory immune response against Mycobacterium tuberculosis (Mtb) is associated with tissue destruction and cavitation, which drives disease transmission, chronic lung disease, and mortality. Matrix metalloproteinase (MMP)-1 is a host enzyme critical for the development of cavitation. MMP expression has been shown to be epigenetically regulated in other inflammatory diseases, but the importance of such mechanisms in Mtb-associated induction of MMP-1 is unknown. We investigated the role of changes in histone acetylation in Mtb-induced MMP expression using inhibitors of histone deacetylases (HDACs) and histone acetyltransferases (HAT), HDAC siRNA, promoter-reporter constructs, and chromatin immunoprecipitation assays. Mtb infection decreased Class I HDAC gene expression by over 50% in primary human monocyte-derived macrophages but not in normal human bronchial epithelial cells (NHBEs). Non-selective inhibition of HDAC activity decreased MMP-1/-3 expression by Mtb-stimulated macrophages and NHBEs, while class I HDAC inhibition increased MMP-1 secretion by Mtb-stimulated NHBEs. MMP-3 expression, but not MMP-1, was downregulated by siRNA silencing of HDAC1. Inhibition of HAT activity also significantly decreased MMP-1/-3 secretion by Mtb-infected macrophages. The MMP-1 promoter region between −2,001 and −2,942 base pairs from the transcriptional start site was key in control of Mtb-driven MMP-1 gene expression. Histone H3 and H4 acetylation and RNA Pol II binding in the MMP-1 promoter region were increased in stimulated NHBEs. In summary, epigenetic modification of histone acetylation via HDAC and HAT activity has a key regulatory role in Mtb-dependent gene expression and secretion of MMP-1 and -3, enzymes which drive human immunopathology. Manipulation of epigenetic regulatory mechanisms may have potential as a host-directed therapy to improve outcomes in the era of rising TB drug resistance.
Highlights
Tuberculosis (TB) remains a major global health problem, with 10.4 million new cases and 1.8 million deaths per year [1]
We demonstrate that Mycobacterium tuberculosis (Mtb) infection alters macrophage Class I histone deacetylases (HDACs) expression and that Matrix metalloproteinase (MMP)-1 expression induced by Mtb is sensitive to HDAC/ histone acetyltransferases (HAT) inhibition
We demonstrated that expression of MMP-1 and -3 in response to Mtb is controlled by epigenetic changes in histone acetylation
Summary
Tuberculosis (TB) remains a major global health problem, with 10.4 million new cases and 1.8 million deaths per year [1]. In vitro studies of airway epithelial cells demonstrated increased HDAC2 expression and decreased histone acetylation in respiratory syncytial virus (RSV)-infected cells, while chemical HDAC inhibition restricted RSV replication [24]. We have investigated whether epigenetic modifications, histone acetylation/deacetylation, regulated the characteristic TB-associated expression of MMP-1 and MMP-3 by monocytederived macrophages and normal human bronchial epithelial cells (NHBEs), thereby augmenting TB immunopathology. The role of histone acetylation in induction of MMP-1/-3 expression was investigated, since this dynamic epigenetic mark is associated with transcriptional activation. Increased histone acetylation was seen at MMP-1 and -3 promoter regions compared with unstimulated cells, in the region −2,001 to −2,942 bp of the MMP-1 promoter, which contains key inducible sites activated in Mtb-stimulated cells
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