Mycobacterium tuberculosis upregulates microglial matrix metalloproteinase-1 and -3 expression and secretion via NF-kappaB- and Activator Protein-1-dependent monocyte networks.
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.
Green
Justin A
JA
Department of Infectious Diseases and Immunity, Hammersmith Campus, Imperial College London, London, United Kingdom. justin.green@imperial.ac.uk
Elkington
Paul T
PT
Pennington
Caroline J
CJ
Roncaroli
Federico
F
Dholakia
Shruti
S
Moores
Rachel C
RC
Bullen
Anwen
A
Porter
Joanna C
JC
Agranoff
Dan
D
Edwards
Dylan R
DR
Friedland
Jon S
JS
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017628:Microglia / Q000276:immunology / Q000378:metabolism*; D018613:Microscopy, Confocal; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020306:Tuberculosis, Central Nervous System / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation
D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D003907:Dexamethasone; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1