Journal
JOURNAL OF IMMUNOLOGY
Volume 184, Issue 11, Pages 6492-6503Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0903811
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Funding
- Royal College of Physicians London, U.K.
- Medical Research Council (U.K.)
- Pathology Society, U.K
- U.K. National Institutes of Health
- Wellcome Trust
- National Institutes of Health Research Biomedical Research Centre
- MRC [G0500385] Funding Source: UKRI
- Medical Research Council [G0500385] Funding Source: researchfish
- National Institute for Health Research [DHCS/06/05/012] Funding Source: researchfish
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Inflammatory tissue destruction is central to pathology in CNS tuberculosis (TB). We hypothesized that microglial-derived matrix metalloproteinases(MMPs) have a key role in driving such damage. Analysis of all of the MMPs demonstrated that conditioned medium from Mycobacterium tuberculosis-infected human monocytes (CoMTb) stimulated greater MMP-1, -3, and -9 gene expression in human microglial cells than direct infection. In patients with CNS TB, MMP-1/-3 immunoreactivity was demonstrated in the center of brain granulomas. Concurrently, CoMTb decreased expression of the inhibitors, tissue inhibitor of metalloproteinase-2, -3, and -4. MMP-1/-3 secretion was significantly inhibited by dexamethasone, which reduces mortality in CNS TB. Surface-enhanced laser desorption ionization time-of-flight analysis of CoMTb showed that TNF-alpha and IL-1 beta are necessary but not sufficient for upregulating MMP-1 secretion and act synergistically to drive MMP-3 secretion. Chemical inhibition and promoter-reporter analyses showed that NF-kappa B and AP-1 c-Jun/FosB heterodimers regulate CoMTb-induced MMP-1/-3 secretion. Furthermore, NF-kappa B p65 and AP-1 c-Jun subunits were upregulated in biopsy granulomas from patients with cerebral TB. In summary, functionally unopposed, network-dependent microglial MMP-1/-3 gene expression and secretion regulated by NF-kappa B and AP-1 subunits were demonstrated in vitro and, for the first time, in CNS TB patients. Dexamethasone suppression of MMP-1/-3 gene expression provides a novel mechanism explaining the benefit of steroid therapy in these patients. The Journal of Immunology, 2010, 184: 6492-6503.
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