The generation of mice lacking both proteinase-3 and neutrophil elastase enabled the authors to explore for the first time the biological relevance of these closely related enzymes. Prtn3−/−Ela2−/− mice developed normal neutrophil populations and, surprisingly, given that these enzymes have been implicated in facilitating cell movement by degrading extracellular matrix components, neutrophil chemotaxis and migration also proved to be unaffected. However, neutrophil infiltration in response to immune-complex deposition (a common occurrence in autoimmune disorders and chronic inflammation) was severely reduced in Prtn3−/−Ela2−/− mice compared with Ela2−/− and wild-type mice. In addition, Prtn3−/−Ela2−/− neutrophils showed impaired production of reactive oxygen species that was induced by tumour-necrosis factor and immune complexes, suggesting a role for these proteases in neutrophil activation.
These observations led the authors to measure the levels of progranulin, a known inhibitor of neutrophil oxidative burst. Importantly, the intact, inhibitory form of progranulin was only found in the supernatants of immune-complex-stimulated Prtn3−/−Ela2−/− neutrophils and not wild-type neutrophils, suggesting that proteinase-3 and neutrophil elastase normally cleave progranulin. The observations that exposure of wild-type neutrophils to recombinant progranulin inhibited their activation; that Prtn3−/−Ela2−/− neutrophils failed to degrade progranulin in vitro and in vivo; and that treatment of inflammatory lesions with recombinant progranulin reduced neutrophil accumulation in both wild-type and Prtn3−/−Ela2−/− mice are all consistent with an important role for serine-protease-mediated progranulin degradation in neutrophilic inflammation.
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