Decreased allergic lung inflammatory cell egression and increased susceptibility to asphyxiation in MMP2-deficiency

Abstract

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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Figure 1: OVA challenge of BALB/c mice induces a robust asthma phenotype and increased MMP2 activity in BAL.
Figure 2: Lung MMP2 is expressed in the presence of allergic inflammation and IL-13.
Figure 3: Effect of MMP inhibition on AHR and BAL cell egression.
Figure 4: Comparison of GM6001 treatment to MMP2 deficiency.
Figure 5: MMP2−/− mice aberrantly accumulate TH2 cytokine mRNA in the lung and show increased susceptibility to lethal asphyxiation.
Figure 6: Aberrant chemotaxis of lung inflammatory cells in response to MMP2−/− BAL.

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Acknowledgements

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.).

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Correspondence to David B. Corry or Farrah Kheradmand.

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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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