Journal
JOURNAL OF NEUROINFLAMMATION
Volume 8, Issue -, Pages -Publisher
BMC
DOI: 10.1186/1742-2094-8-46
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Funding
- Royal College of Physicians London, UK
- MRC [G0500385]
- Pathology Society, UK
- Wellcome Trust
- NIHR Biomedical Research Centre
- Imperial College Wellcome Centre for Clinical Tropical Medicine
- 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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Tuberculosis (TB) of the central nervous system (CNS) is a deadly disease characterized by extensive tissue destruction, driven by molecules such as Matrix Metalloproteinase-2 (MMP-2) which targets CNS-specific substrates. In a simplified cellular model of CNS TB, we demonstrated that conditioned medium from Mycobacterium tuberculosis-infected primary human monocytes (CoMTb), but not direct infection, unexpectedly down-regulates constitutive microglial MMP-2 gene expression and secretion by 72.8% at 24 hours, sustained up to 96 hours (P < 0.01), dependent upon TNF-alpha. In human CNS TB brain biopsies but not controls the p38 pathway was activated in microglia/macrophages. Inhibition of the p38 MAP kinase pathway resulted in a 228% increase in MMP-2 secretion (P < 0.01). In contrast ERK MAP kinase inhibition further decreased MMP-2 secretion by 76.6% (P < 0.05). Inhibition of the NF kappa B pathway resulted in 301% higher MMP-2 secretion than CoMTb alone (P < 0.01). Caspase 8 restored MMP-2 secretion to basal levels. However, this caspase-dependent regulation of MMP-2 was independent of p38 and NF kappa B pathways; p38 phosphorylation was increased and p50/p65 NF kappa B nuclear trafficking unaffected by caspase 8 inhibition. In summary, suppression of microglial MMP-2 secretion by M.tb-infected monocyte-dependent networks paradoxically involves the pro-inflammatory mediators TNF-alpha, p38 MAP kinase and NF kappa B in addition to a novel caspase 8-dependent pathway.
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