Abstract
The importance of neutrophils in the pathology of tuberculosis (TB) has been recently established. We demonstrated that TB lesions in man are hypoxic, but how neutrophils in hypoxia influence lung tissue damage is unknown. We investigated the effect of hypoxia on neutrophil-derived enzymes and tissue destruction in TB. Human neutrophils were stimulated with M. tuberculosis (M.tb) or conditioned media from M.tb-infected monocytes (CoMTB). Neutrophil matrix metalloproteinase-8/-9 and elastase secretion were analysed by luminex array and gelatin zymography, gene expression by qPCR and cell viability by flow cytometry. Matrix destruction was investigated by confocal microscopy and functional assays and neutrophil extracellular traps (NETs) by fluorescence assay. In hypoxia, neutrophil MMP-8 secretion and gene expression were up-regulated by CoMTB. MMP-9 activity and neutrophil elastase (NE) secretion were also increased in hypoxia. Hypoxia inhibited NET formation and both neutrophil apoptosis and necrosis after direct stimulation by M.tb. Hypoxia increased TB-dependent neutrophil-mediated matrix destruction of Type I collagen, gelatin and elastin, the main structural proteins of the human lung. Dimethyloxalylglycin (DMOG), which stabilizes hypoxia-inducible factor-1α, increased neutrophil MMP-8 and -9 secretion. Hypoxia in our cellular model of TB up-regulated pathways that increase neutrophil secretion of MMPs that are implicated in matrix destruction.
Highlights
The clinical features of tuberculosis (TB) are increasingly recognised to be mediated by the host innate immune response[1,2,3]
Hypoxia increases TB-driven neutrophil collagenase (MMP-8) and neutrophil elastase secretion
We investigated the impact of hypoxia on neutrophil-dependent tissue destruction in TB and show that hypoxia increases matrix metalloproteinases (MMPs)-8 and neutrophil elastase secretion in the presence of conditioned media from M.tb-infected monocytes (CoMTB) but not with M.tb stimulation
Summary
The clinical features of tuberculosis (TB) are increasingly recognised to be mediated by the host innate immune response[1,2,3]. We show that hypoxia increases neutrophil MMP-8, -9 and neutrophil elastase secretion in TB, which drive matrix destruction. Results Hypoxia increases TB-driven neutrophil collagenase (MMP-8) and neutrophil elastase secretion.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
