Clearance of recruited immune cells is necessary to resolve inflammatory reactions. We show here that matrix metalloproteinase 2 (MMP2), as part of an interleukin 13 (IL-13)–dependent regulatory loop, dampens inflammation by promoting the egress of inflammatory cells into the airway lumen. MMP2−/− mice showed a robust asthma phenotype and increased susceptibility to asphyxiation induced by allergens. However, whereas the lack of MMP2 reduced the influx of cells into bronchoalveolar lavage (BAL), numerous inflammatory cells accumulated in the lung parenchyma. BAL of MMP2−/− mice lacked normal chemotactic activity, whereas lung inflammatory cells from the same mice showed appropriate chemotactic responses. Thus, MMP2 establishes the chemotactic gradient required for egression of lung inflammatory cells and prevention of lethal asphyxiation.
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Barnes, P. J. Pathophysiology of asthma. Br. J. Clin. Pharmacol. 42, 3–10 (1996).
Coyle, A. J. et al. Interleukin-4 is required for the induction of lung Th2 mucosal immunity. Am. J. Respir. Cell Mol. Biol. 13, 54–59 (1995).
Corry, D. B. et al. Interleukin 4, but not interleukin 5 or eosinophils, is required in a murine model of acute airway hyperreactivity. J. Exp. Med. 183, 109–117 (1996).
Foster, P. S., Hogan, S. P., Ramsay, A. J., Matthaei, K. I. & Young, I. G. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J. Exp. Med. 183, 195–201 (1996).
Corry, D. B. et al. Requirements for allergen- induced airway hyperreactivity in T and B cell– deficient mice. Mol. Med. 4, 344–355 (1998).
Robinson, D. S. et al. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N. Engl. J. Med. 326, 298–304 (1992).
Barnes, P. J. & Page, C. Mediators of asthma: a new series. Pulm. Pharmacol. Ther. 14, 1–2 (2001).
Swain, S. L., Weinberg, A. D., English, M. & Huston, G. IL-4 directs the development of Th2-like helper effectors. J. Immunol. 145, 3796–3806 (1990).
Kopf, M. et al. Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature 362, 245–248 (1993).
Finkelman, F. D. et al. IL-4 is required to generate and sustain in vivo IgE responses. J. Immunol. 141, 2335–2341 (1988).
Murata, T., Obiri, N. I., Debinski, W. & Puri, R. K. Structure of IL-13 receptor: analysis of subunit composition in cancer and immune cells. Biochem. Biophys. Res. Commun. 238, 90–94 (1997).
Miloux, B. et al. Cloning of the human IL-13Rα chain and reconstitution with the IL4Rα of a functional IL-4/IL-13 receptor complex. FEBS Lett. 401, 163–166 (1997).
Hilton, D. J. et al. Cloning and characterization of a binding subunit of the interleukin 13 receptor that is also a component of the interleukin 4 receptor. Proc. Natl Acad. Sci. USA 93, 497–501 (1996).
Grunig, G. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–2263 (1998).
Corry, D. B. IL-13 in allergy: home at last. Curr. Opin. Immunol. 11, 610–614 (1999).
Doucet, C. et al. Interleukin (IL) 4 and IL-13 act on human lung fibroblasts. Implication in asthma. J. Clin. Invest. 101, 2129–2139 (1998).
Becky Kelly, E. A., Busse, W. W. & Jarjour, N. N. Increased matrix metalloproteinase-9 in the airway after allergen challenge. Am. J. Resp. Crit. Care Med. 162, 1157–1161 (2000).
Zheng, T. et al. Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsin-dependent emphysema. J. Clin. Invest. 106, 1081–1093 (2000).
Kumagai, K. et al. Inhibition of matrix metalloproteinases prevents allergen-induced airway inflammation in a murine model of asthma. J. Immunol. 162, 4212–4219 (1999).
Holla, L. I., Vasku, A., Stejskalova, A. & Znojil, V. Functional polymorphism in the gelatinase B gene and asthma. Allergy 55, 900–901 (2000).
Cataldo, D. et al. MMP2- and MMP-9-linked gelatinolytic activity in the sputum from patients with asthma and chronic obstructive pulmonary disease. Int. Arch. Allergy Immunol. 123, 259–267 (2000).
Haas, T. L. & Madri, J. A. Extracellular matrix-driven matrix metalloproteinase production in endothelial cells: implications for angiogenesis. Trends Cardiovasc. Med. 9, 70–77 (1999).
Madri, J. A., Graesser, D. & Haas, T. The roles of adhesion molecules and proteinases in lymphocyte transendothelial migration. Biochem. Cell Biol. 74, 749–757 (1996).
Goldstein, R. A., Paul, W. E., Metcalfe, D. D., Busse, W. W. & Reece, E. R. NIH conference. Asthma. Ann. Intern. Med. 121, 698–708 (1994).
Galardy, R. E., Grobelny, D., Foellmer, H. G. & Fernandez, L. A. Inhibition of angiogenesis by the matrix metalloprotease inhibitor N-[2R-2-(hydroxamidocarbonymethyl)-4-methylpentanoyl)]-l-tryptophan methylamide. Cancer Res. 54, 4715–4718 (1994).
Itoh, T. et al. Unaltered secretion of β-amyloid precursor protein in gelatinase A (matrix metalloproteinase 2)-deficient mice. J. Biol. Chem. 272, 22389–22392 (1997).
Grunig, G. et al. Interleukin-10 is a natural suppressor of cytokine production and inflammation in a murine model of allergic bronchopulmonary aspergillosis. J. Exp. Med. 185, 1089–1099 (1997).
Baggiolini, M. Reflections on chemokines. Immunol. Rev. 177, 5–7 (2000).
Mathew, A. et al. Signal transducer and activator of transcription 6 controls chemokine production and T helper cell type 2 cell trafficking in allergic pulmonary inflammation. J. Exp. Med. 193, 1087–1096 (2001).
Lilly, C. M. et al. Eotaxin expression after segmental allergen challenge in subjects with atopic asthma. Am. J. Respir. Crit. Care Med. 163, 1669–1675 (2001).
Lamkhioued, B. et al. Increased expression of eotaxin in bronchoalveolar lavage and airways of asthmatics contributes to the chemotaxis of eosinophils to the site of inflammation. J. Immunol. 159, 4593–4601 (1997).
Sears, M. R. Consequences of long-term inflammation. The natural history of asthma. Clin. Chest Med. 21, 315–329 (2000).
Betsuyaku, T., Shipley, J. M., Liu, Z. & Senior, R. M. Neutrophil emigration in the lungs, peritoneum, and skin does not require gelatinase B. Am. J. Respir. Cell Mol. Biol. 20, 1303–1309 (1999).
Milik, A. M. et al. Lung lymphocyte elimination by apoptosis in the murine response to intratracheal particulate antigen. J. Clin. Invest. 99, 1082–1091 (1997).
Savill, J. Apoptosis in resolution of inflammation. Kidney Blood Press. Res. 23, 173–174 (2000).
Savill, J. & Fadok, V. Corpse clearance defines the meaning of cell death. Nature 407, 784–788 (2000).
Bancroft, A. J., Artis, D., Donaldson, D. D., Sypek, J. P. & Grencis, R. K. Gastrointestinal nematode expulsion in IL-4 knockout mice is IL-13 dependent. Eur. J. Immunol. 30, 2083–2091 (2000).
Dubois, G. R. & Bruijnzeel, P. L. IL-4-induced migration of eosinophils in allergic inflammation. Ann NY Acad. Sci. 725, 268–273 (1994).
Azzawi, M., Johnston, P. W., Majumdar, S., Kay, A. B. & Jeffery, P. K. T lymphocytes and activated eosinophils in airway mucosa in fatal asthma and cystic fibrosis. Am. Rev. Respir. Dis. 145, 1477–1482 (1992).
Kikuchi, Y. et al. Chemosensitivity and perception of dyspnea in patients with a history of near-fatal asthma. N. Engl. J. Med. 330, 1329–1334 (1994).
Molfino, N. A., Nannini, L. J., Martelli, A. N. & Slutsky, A. S. Respiratory arrest in near-fatal asthma. N. Engl. J. Med. 324, 285–288 (1991).
McQuibban, G. A. et al. Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3. Science 289, 1202–1206 (2000).
Okada, S., Kita, H., George, T. J., Gleich, G. J. & Leiferman, K. M. Migration of eosinophils through basement membrane components in vitro: role of matrix metalloproteinase-9. Am. J. Respir. Cell Mol. Biol. 17, 519–528 (1997).
Reponen, P. et al. Molecular cloning of murine 72-kDa type IV collagenase and its expression during mouse development. J. Biol. Chem. 267, 7856–7862 (1992).
Alexander, C. M. et al. Expression and function of matrix metalloproteinases and their inhibitors at the maternal-embryonic boundary during mouse embryo implantation. Development 122, 1723–1736 (1996).
Chin, J. R. & Werb, Z. Matrix metalloproteinases regulate morphogenesis, migration and remodeling of epithelium, tongue skeletal muscle and cartilage in the mandibular arch. Development 124, 1519–1530 (1997).
Chen, S. et al. In vivo inhibition of CC and CX3C chemokine-induced leukocyte infiltration and attenuation of glomerulonephritis in Wistar-Kyoto (WKY) rats by vMIP-II. J. Exp. Med. 188, 193–198 (1998).
Wu, J. Y. et al. The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors. Nature 410, 948–952 (2001).
We thank A. C. White and B. Dickey for helpful comments and T. Itoh and S. Itohara for providing the MMP2−/− mice. Supported by the Caroline Weiss Law Fund for Molecular Medicine; National Institutes of Health grants K08 HL03344 and R01 HL69585 (to D. C.), K08 HL03732 and R01 HL64061 (to F. K.); and the Sandler Family Asthma Fund (to Z. W.).
The authors declare no competing financial interests.
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Corry, D., Rishi, K., Kanellis, J. et al. Decreased allergic lung inflammatory cell egression and increased susceptibility to asphyxiation in MMP2-deficiency. Nat Immunol 3, 347–353 (2002). https://doi.org/10.1038/ni773
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