Complex regulation of neutrophil-derived MMP-9 secretion in central nervous system tuberculosis

Background: central nervous system tuberculosis (cns-tb) may be fatal even with treatment. neutrophils are the key mediators of tb immunopathology,and raised csf matrix metalloproteinase-9 (mmp-9) which correlates to neutrophil count in cns-tb is associated with neurological deficit and death. the mechanisms by which neutrophils drive tb-associated cns matrix destruction are not clearly defined. methods: human brain biopsies with histologically proven cns-tb were stained for neutrophils,neutrophil elastase,and mmp-9. neutrophil mmp-9 secretion and gene expression were analyzed using luminex and real-time pcr. type iv collagen degradation was evaluated using confocal microscopy and quantitative fluorescent assays. intracellular signaling pathways were investigated by immunoblotting and chemical inhibitors. results: mmp-9-expressing neutrophils were present in tuberculous granulomas in cns-tb and neutrophil-derived mmp-9 secretion was upregulated by mycobacterium tuberculosis (m.tb). concurrent direct stimulation by m.tb and activation via monocyte-dependent networks had an additive effect on neutrophil mmp-9 secretion. destruction of type iv collagen,a key component of the blood-brain barrier,was inhibited by neutralizing neutrophil mmp-9. monocyte-neutrophil networks driving mmp-9 secretion in tb were regulated by map-kinase and akt-pi3 kinase pathways and the transcription factor nf-kb. tnfα neutralization suppressed mmp-9 secretion to baseline while dexamethasone did not. conclusions: multiple signaling paths regulate neutrophil-derived mmp-9 secretion,which is increased in cns-tb. these paths may be better targets for host-directed therapies than steroids currently used in cns-tb. © 2017 the author(s).