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Mycobacterium tuberculosis upregulates microglial matrix metalloproteinase-1 and -3 expression and secretion via
Justin A Green1, Paul T Elkington, Caroline J Pennington
1Department of Infectious Diseases and Immunity, Hammersmith Campus, Imperial College London, London, United Kingdom. justin.green@imperial.ac.uk
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-alpha and IL-1beta 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-kappaB and AP-1 c-Jun/FosB heterodimers regulate CoMTb-induced MMP-1/-3 secretion. Furthermore, NF-kappaB 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-kappaB 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.
Insights
Microglial matrix metalloproteinases (MMPs) drive central nervous system (CNS) tuberculosis (TB) tissue damage. Dexamethasone suppresses MMP-1/-3, explaining steroid therapy benefits in CNS TB patients.
Area of Science:
- Neuroimmunology
- Molecular Biology
- Infectious Diseases
Background:
- Central nervous system tuberculosis (CNS TB) involves significant inflammatory tissue destruction.
- Microglia, the resident immune cells of the brain, are implicated in this pathology.
- Matrix metalloproteinases (MMPs) are enzymes capable of degrading extracellular matrix, potentially contributing to tissue damage.
Purpose of the Study:
- To investigate the role of microglial-derived matrix metalloproteinases (MMPs) in the pathogenesis of CNS tuberculosis (TB).
- To elucidate the molecular mechanisms regulating MMP expression and secretion in response to Mycobacterium tuberculosis infection.
- To explore the therapeutic potential of targeting MMPs in CNS TB.
Main Methods:
- Cultured human microglial cells were stimulated with conditioned medium from Mycobacterium tuberculosis-infected monocytes (CoMTb).
- Gene expression of MMPs and their inhibitors was analyzed using quantitative PCR.
- Immunohistochemistry was performed on brain granulomas from CNS TB patients.
- Protein secretion was assessed, and molecular pathways (NF-kappaB, AP-1) were investigated using chemical inhibition and reporter assays.
Main Results:
- CoMTb significantly upregulated MMP-1, -3, and -9 gene expression in microglial cells.
- MMP-1/-3 immunoreactivity was observed in brain granulomas of CNS TB patients.
- Dexamethasone treatment significantly inhibited MMP-1/-3 secretion.
- Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were necessary for MMP-1 and synergistic for MMP-3 secretion.
- NF-kappaB and AP-1 signaling pathways were identified as key regulators of CoMTb-induced MMP secretion.
Conclusions:
- Microglial MMP-1 and MMP-3 play a crucial role in the inflammatory tissue destruction seen in CNS TB.
- The NF-kappaB and AP-1 signaling pathways are critical for regulating microglial MMP production in response to M. tuberculosis.
- Dexamethasone's ability to suppress microglial MMP expression provides a novel mechanistic explanation for its therapeutic efficacy in CNS TB.
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