Title

Mycobacterial Trehalose Dimycolate Reprograms Macrophage Global Gene Expression and Activates Matrix Metalloproteinases

Authors

Authors

K. Sakamoto; M. J. Kim; E. R. Rhoades; R. E. Allavena; S. Ehrt; H. C. Wainwright; D. G. Russell;K. H. Rohde

Comments

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Abbreviated Journal Title

Infect. Immun.

Keywords

CORD FACTOR TREHALOSE-6, 6'-DIMYCOLATE; NECROSIS-FACTOR-ALPHA; CELL-WALL; LIPIDS; GRANULOMATOUS RESPONSE; TISSUE INHIBITORS; IMMUNE-RESPONSE; MYCOLIC ACIDS; IN-VIVO; ANTISENSE OLIGONUCLEOTIDES; TUBERCULOSIS; INFECTION; Immunology; Infectious Diseases

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-mu m-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.

Journal Title

Infection and Immunity

Volume

81

Issue/Number

3

Publication Date

1-1-2013

Document Type

Article

Language

English

First Page

764

Last Page

776

WOS Identifier

WOS:000316313200018

ISSN

0019-9567

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