Editors' ChoiceInflammation

Controlled Cofactor Release Attracts Neutrophils

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Science's STKE  10 Dec 2002:
Vol. 2002, Issue 162, pp. tw458-TW458
DOI: 10.1126/stke.2002.162.tw458

Epithelia form an essential barrier protecting the body's surfaces from the outside. Trauma or infection that damages this barrier stimulates the epithelia to undergo processes that promote tissue repair and recruit inflammatory mediators to the site of injury. Li et al. examined the response of mice deficient for MAT, the gene encoding the matrix metalloproteinase MMP-7 (also known as matrilysin), in response to bleomycin instillation in the lung, which in wild-type animals causes alveolar epithelial damage, inflammation, fibrosis, and eventually death. Unexpectedly, bleomycin caused less tissue damage and less mortality in the MAT-/- mice as compared to the wild type. This was due to defective transepithelial migration of neutrophils into the alveolar lumen. Addition of a chemoattractant with bleomycin resulted in increased mortality and inflammation in the MAT-/-mice, suggesting a defect in chemoattractant signaling. Indeed, lung lavage from the bleomycin-treated MAT-/- mice had less KC--the mouse homolog of interleukin 18 (IL-18), a potent neutrophil chemoattractant--despite having similar overall levels of KC in total lung extracts as wild-type mice. IL-18 requires heparan sulfate for chemoattraction activity. A soluble form of syndecan-1, a heparan sulfate proteoglycan of the epithelial surface, was produced in lungs of wild-type mice treated with bleomycin but not in the MAT-/- mice. Thus, activation of MMP in response to epithelial injury triggered the release of cofactors (syndecan-1) that can control the activity of ligands (chemoattractants such as IL-18), allowing localized signaling at the site of epithelial injury.

Q. Li, P. W. Park., C. L. Wilson, W. C. Parks, Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 111, 635-646 (2002). [Online Journal]

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