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Interleukin-13–Dependent Expression of Matrix Metalloproteinase-12 Is Required for the Development of Airway Eosinophilia in Mice

Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada; MRC Laboratory of Molecular Biology, Cambridge, United Kingdom; and Department of Respiratory Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

Address correspondence to: Martin R. Stämpfli, Ph.D., McMaster University, Department of Pathology and Molecular Medicine, Health Sciences Centre, Room 4H21A, 1200 Main Street West, Hamilton, ON, L8N 3Z5 Canada. E-mail: stampfli{at}mcmaster.ca

We investigated the expression and function of matrix metalloproteinase-12 (MMP-12) in a model of allergic airway inflammation. Mice were sensitized mucosally by exposure to aerosolized ovalbumin (OVA) daily over a period of 10 d in the context of adenovirus-mediated granulocyte macrophage colony-stimulating factor (GM-CSF) expression. The ensuing inflammatory response is characterized by a Th2 cytokine profile, OVA-specific IgE, and airway eosinophilia. Using real-time, quantitative reverse transcriptase–polymerase chain reaction we assessed MMP-12 mRNA expression in whole lung tissue. We observed a 12- and 70-fold increase in expression at Days 7 and 11, respectively, in OVA-exposed mice when compared with naive controls. Immunoblot analysis revealed an increase in MMP-12 protein in the bronchoalveolar lavage fluid of mice exposed to OVA in the context of GM-CSF. No such elevation was observed in mice exposed to saline only in the context of GM-CSF. To assess functional role of MMP-12, MMP-12 knockout (KO) mice were subjected to the aforementioned protocol. We observed an 80% reduction in eosinophils in the bronchoalveolar lavage fluid of KO mice compared with their wild-type littermates. Using interleukin-13 KO mice, we demonstrated that expression of MMP-12 is interleukin-13–dependent. Collectively, our data indicate a novel function for MMP-12 in the process of airway eosinophil accumulation.

Abbreviations: alveolar macrophage, AM • bronchoalveolar lavage, BAL • enzyme-linked immunosorbent assay, ELISA • granulocyte macrophage colony-stimulating factor, GM-CSF • interleukin, IL • knockout, KO • matrix metalloproteinase, MMP • ovalbumin, OVA • phosphate-buffered saline, PBS • recombinant GM-CSF, rGM-CSF • recombinant IL, rIL • saline, SAL • tissue inhibitor of matrix metalloproteinase, TIMP • wild-type, WT

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