title: Mycobacterial trehalose dimycolate reprograms macrophage global gene expression and activates matrix metalloproteinases.
abstract: Trehalose 6,6'-dimycolate (TDM) is a cell wall glycolipid and an important virulence factor of mycobacteria. In order to study the role of TDM in the innate immune response to Mycobacterium tuberculosis, microarray analysis was used to examine gene regulation in murine bone marrow-derived macrophages in response to 90-μm-diameter polystyrene microspheres coated with TDM. A large number of genes, particularly those involved in the immune response and macrophage function, were up- or downregulated in response to these TDM-coated beads compared to control beads. Genes involved in the immune response were specifically upregulated in a myeloid differentiation primary response gene 88 (MyD88)-dependent manner. The complexity of the transcriptional response also increased greatly between 2 and 24 h. Matrix metalloproteinases (MMPs) were significantly upregulated at both time points, and this was confirmed by quantitative real-time reverse transcription-PCR (RT-PCR). Using an in vivo Matrigel granuloma model, the presence and activity of MMP-9 were examined by immunohistochemistry and in situ zymography (ISZ), respectively. We found that TDM-coated beads induced MMP-9 expression and activity in Matrigel granulomas. Macrophages were primarily responsible for MMP-9 expression, as granulomas from neutrophil-depleted mice showed staining patterns similar to that for wild-type mice. The relevance of these observations to human disease is supported by the similar induction of MMP-9 in human caseous tuberculosis (TB) granulomas. Given that MMPs likely play an important role in both the construction and breakdown of tuberculous granulomas, our results suggest that TDM may drive MMP expression during TB pathogenesis.
authors.affiliation: Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA. kaoris@uga.edu
authors.forename: Kaori
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Mi Jeong
authors.initials: MJ
authors.lastname: Kim
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Rhoades
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Allavena
authors.forename: Sabine
authors.initials: S
authors.lastname: Ehrt
authors.forename: Helen C
authors.initials: HC
authors.lastname: Wainwright
authors.forename: David G
authors.initials: DG
authors.lastname: Russell
authors.forename: Kyle H
authors.initials: KH
authors.lastname: Rohde
mesh_terms: D000818:Animals; D003311:Cord Factors / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006099:Granuloma / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D003311:Cord Factors; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012313:RNA; D020782:Matrix Metalloproteinases