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Green, Justin A., Elkington, Paul T., Pennington, Caroline J., Roncaroli, Federico, Dholakia, Shruti, Moores, Rachel C., Bullen, Anwen, Porter, Joanna C., Agranoff, Dan, Edwards, Dylan R. 
ORCID: https://orcid.org/0000-0002-3292-2064 and Friedland, Jon S.
(2010)
Mycobacterium tuberculosis upregulates microglial matrix metalloproteinase-1 and -3 expression and secretion via NF- B- and activator protein-1-dependent monocyte networks.
Journal of Immunology, 184 (11).
pp. 6492-6503.
ISSN 0022-1767
Abstract
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-α and IL-1β 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-κB and AP-1 c-Jun/FosB heterodimers regulate CoMTb-induced MMP-1/-3 secretion. Furthermore, NF-κB 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-κB 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being |
| Faculty \ School: | Faculty of Science > School of Biological Sciences |
| UEA Research Groups: | Faculty of Science > Research Groups > Cells and Tissues Faculty of Medicine and Health Sciences > Research Groups > Cancer Studies |
| Depositing User: | Users 2731 not found. |
| Date Deposited: | 07 Feb 2011 10:52 |
| Last Modified: | 14 Jul 2023 15:30 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/21023 |
| DOI: | 10.4049/jimmunol.0903811 |
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