Epigenetic Regulation of Matrix Metalloproteinase-1 and -3 Expression in Mycobacterium tuberculosis Infection

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.

Functional Inhibition of Host Histone Deacetylases (HDACs) Enhances in vitro and in vivo Anti-mycobacterial Activity in Human Macrophages and in Zebrafish

“…Here, we report that histone deacetylase (HDAC) transcriptomic levels are strongly affected by Mtb-infection in primary human macrophages. Secondly, we report that broad chemical HDAC inhibition can enhance the antimicrobial response of both (16,18,19). In this study, we observed that following Mtb infection, transcriptional levels of several HDACs representing different classes were differentially regulated in Mφ1 but primarily in Mφ2.…”

“…Granuloma formation in the lungs of TB infected individuals is driven by macrophages and the resulting outcome of infection, i.e., bacterial control or bacterial dissemination, relies on macrophage type, and polarization (14,15). It is therefore not surprising that several pathogens, including Mtb have been implicated in evading the immune system by modulating histone acetylation via altering HDAC expression levels (11,(16)(17)(18)(19).…”

Sodium Butyrate Abrogates the Growth and Pathogenesis of Mycobacterium bovis via Regulation of Cathelicidin (LL37) Expression and NF-κB Signaling

“…By regulating the acetylation of histones, HDAC can regulate the expression of various gene and key biological process, including gene responsible for the production of inflammatory cytokines and its signaling pathways (Zhang et al, 2015). It has been reported that matrix metalloproteinase (MMP)-1 and -3 expression were regulated by HDAC in M. tuberculosis infection (Moores et al, 2017). In addition, HDAC1 can regulate the expression of iNOS and many cytokines (Calegari-Silva et al, 2018).…”

Intravenous antagomiR-494 lessens brain-infiltrating neutrophils by increasing HDAC2-mediated repression of multiple MMPs in experimental stroke

“…Noticeably, HDAC2 could bind to different loci on chromosome 11 and can modulate MMP27 bidirectionally. Previous studies suggested that the HDAC family could regulate multiple MMPs, including MMP1, MMP2, MMP3, MMP7, MMP9, MMP10, MMP13, MMP14, and MMP28 [20][21][22][23][24][25], and that MMP10 could be regulated by HDAC3 and HDAC7 [25,26]. For the first time, we found that HDAC2 could potentially modulate the MMP10, MMP16, MMP21, MMP25-AS1, and MMP27 genes in neutrophils of AIS patients.…”