title: Mycobacterium tuberculosis-infected human monocytes down-regulate microglial MMP-2 secretion in CNS tuberculosis via TNFα, NFκB, p38 and caspase 8 dependent pathways.
abstract: 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-α. 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 NFκB 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 NFκB pathways; p38 phosphorylation was increased and p50/p65 NFκB 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-α, p38 MAP kinase and NFκB in addition to a novel caspase 8-dependent pathway.
authors.affiliation: Section of Infectious Diseases and Immunity and the Imperial College Wellcome Trust Centre for Clinical Tropical Medicine, Hammersmith Campus, Imperial College London, London, W12 0NN, UK. justin.green@imperial.ac.uk
authors.forename: Justin A
authors.initials: JA
authors.lastname: Green
authors.forename: Shruti
authors.initials: S
authors.lastname: Dholakia
authors.forename: Karolina
authors.initials: K
authors.lastname: Janczar
authors.forename: Catherine Wm
authors.initials: CW
authors.lastname: Ong
authors.forename: Rachel
authors.initials: R
authors.lastname: Moores
authors.forename: Julie
authors.initials: J
authors.lastname: Fry
authors.forename: Paul T
authors.initials: PT
authors.lastname: Elkington
authors.forename: Federico
authors.initials: F
authors.lastname: Roncaroli
authors.forename: Jon S
authors.initials: JS
authors.lastname: Friedland
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D017077:Culture Media, Conditioned / Q000737:chemistry; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D017628:Microglia / Q000166:cytology / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology*; D009169:Mycobacterium tuberculosis / Q000378:metabolism / Q000472:pathogenicity; D016328:NF-kappa B / Q000378:metabolism*; D012717:Sesquiterpenes / Q000378:metabolism; D045789:Sesquiterpenes, Guaiane; D015398:Signal Transduction / Q000502:physiology; D020306:Tuberculosis, Central Nervous System / Q000378:metabolism* / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D017077:Culture Media, Conditioned; D016328:NF-kappa B; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; D014409:Tumor Necrosis Factor-alpha; C001329:helenalin; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D053181:Caspase 8; D020778:Matrix Metalloproteinase 2