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Title: Integrin à2?1 expression regulates matrix metalloproteinase-1-dependent bronchial epithelial repair in pulmonary tuberculosis
Authors: Brilha S.
Chong D.L.W.
Khawaja A.A.
Ong C.W.M. 
Guppy N.J.
Porter J.C.
Friedland J.S.
Keywords: Extracellular matrix; Integrins; Matrix metalloproteinases; Respiratory epithelial cell; Tuberculosis
Issue Date: 2018
Publisher: Frontiers Media S.A.
Citation: Brilha S., Chong D.L.W., Khawaja A.A., Ong C.W.M., Guppy N.J., Porter J.C., Friedland J.S. (2018). Integrin à2?1 expression regulates matrix metalloproteinase-1-dependent bronchial epithelial repair in pulmonary tuberculosis. Frontiers in Immunology 9 (JUN) : 1348. ScholarBank@NUS Repository.
Abstract: Pulmonary tuberculosis (TB) is caused by inhalation of Mycobacterium tuberculosis, which damages the bronchial epithelial barrier to establish local infection. Matrix metalloproteinase-1 plays a crucial role in the immunopathology of TB, causing breakdown of type I collagen and cavitation, but this collagenase is also potentially involved in bronchial epithelial repair. We hypothesized that the extracellular matrix (ECM) modulates M. tuberculosis-driven matrix metalloproteinase-1 expression by human bronchial epithelial cells (HBECs), regulating respiratory epithelial cell migration and repair. Medium from monocytes stimulated with M. tuberculosis induced collagenase activity in bronchial epithelial cells, which was reduced by ~87% when cells were cultured on a type I collagen matrix. Matrix metalloproteinase-1 had a focal localization, which is consistent with cell migration, and overall secretion decreased by 32% on type I collagen. There were no associated changes in the specific tissue inhibitors of metalloproteinases. Decreased matrix metalloproteinase-1 secretion was due to ligand-binding to the à2?1 integrin and was dependent on the actin cytoskeleton. In lung biopsies, samples from patients with pulmonary TB, integrin à2?1 is highly expressed on the bronchial epithelium. Areas of lung with disrupted collagen matrix showed an increase in matrix metalloproteinases-1 expression compared with areas where collagen was comparable to control lung. Type I collagen matrix increased respiratory epithelial cell migration in a wound-healing assay, and this too was matrix metalloproteinase-dependent, since it was blocked by the matrix metalloproteinase inhibitor GM6001. In summary, we report a novel mechanism by which à2?1-mediated signals from the ECM modulate matrix metalloproteinase-1 secretion by HBECs, regulating their migration and epithelial repair in TB. ? 2018 Brilha, Chong, Khawaja, Ong, Guppy, Porter and Friedland.
Source Title: Frontiers in Immunology
ISSN: 16643224
DOI: 10.3389/fimmu.2018.01348
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