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Divergent functions for airway epithelial matrix metalloproteinase 7 and retinoic acid in experimental asthma

Nature Immunology volume 10, pages 496–503 (2009)Cite this article

Abstract

The innate immune response of airway epithelial cells to airborne allergens initiates the development of T cell responses that are central to allergic inflammation. Although proteinase allergens induce the expression of interleukin 25, we show here that epithelial matrix metalloproteinase 7 (MMP7) was expressed during asthma and was required for the maximum activity of interleukin 25 in promoting the differentiation of T helper type 2 cells. Allergen-challenged Mmp7−/− mice had less airway hyper-reactivity and production of allergic inflammatory cytokines and higher expression of retinal dehydrogenase 1. Inhibition of retinal dehydrogenase 1 restored the asthma phenotype of Mmp7−/− mice and inhibited the responses of lung regulatory T cells, whereas exogenous administration of retinoic acid attenuated the asthma phenotype. Thus, MMP7 coordinates allergic lung inflammation by activating interleukin 25 while simultaneously inhibiting retinoid-dependent development of regulatory T cells.

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Figure 1: MMP7 is induced in allergic inflammation and modulates IL-25 function.
Figure 2: MmP7−/− mice have an attenuated asthma phenotype.
Figure 3: Attenuated TH2 cytokines and chemokines in Mmp7−/− mice.
Figure 4: Proteomics analysis of BAL fluid from CAA-immunized wild-type and Mmp7−/− mice.
Figure 5: Epithelial expression of RALDH-1 in response to allergens initiates a negative regulatory response.
Figure 6: Expression of MMP7 and IL-25 in humans with asthma.

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References

  1. Kheradmand, F. et al. A protease-activated pathway underlying Th cell type 2 activation and allergic lung disease. J. Immunol. 169, 5904–5911 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Kiss, A. et al. A new mechanism regulating the initiation of allergic airway inflammation. J. Allergy Clin. Immunol. 120, 334–342 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Li, L. et al. Effects of Th2 cytokines on chemokine expression in the lung: IL-13 potently induces eotaxin expression by airway epithelial cells. J. Immunol. 162, 2477–2487 (1999).

    CAS  PubMed  Google Scholar 

  4. Zhu, J. et al. Exacerbations of bronchitis: bronchial eosinophilia and gene expression for interleukin-4, interleukin-5, and eosinophil chemoattractants. Am. J. Respir. Crit. Care Med. 164, 109–116 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Angkasekwinai, P. et al. Interleukin 25 promotes the initiation of proallergic type 2 responses. J. Exp. Med. 204, 1509–1517 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Moseley, T.A., Haudenschild, D.R., Rose, L. & Reddi, A.H. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 14, 155–174 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Pan, G. et al. Forced expression of murine IL-17E induces growth retardation, jaundice, a Th2-biased response, and multiorgan inflammation in mice. J. Immunol. 167, 6559–6567 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Kim, M.R. et al. Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production. Blood 100, 2330–2340 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Ballantyne, S.J. et al. Blocking IL-25 prevents airway hyperresponsiveness in allergic asthma. J. Allergy Clin. Immunol. 120, 1324–1331 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Fallon, P.G. et al. Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion. J. Exp. Med. 203, 1105–1116 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Greenlee, K.J., Werb, Z. & Kheradmand, F. Matrix metalloproteinases in lung: multiple, multifarious, and multifaceted. Physiol. Rev. 87, 69–98 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Dong, C. TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat. Rev. Immunol. 8, 337–348 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Parks, W.C., Wilson, C.L. & Lopez-Boado, Y.S. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat. Rev. Immunol. 4, 617–629 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. McMillan, S.J. et al. Matrix metalloproteinase-9 deficiency results in enhanced allergen-induced airway inflammation. J. Immunol. 172, 2586–2594 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Corry, D.B. et al. Overlapping and independent contributions of MMP2 and MMP9 to lung allergic inflammatory cell egression through decreased CC chemokines. FASEB J. 18, 995–997 (2004).

    Article  CAS  PubMed  Google Scholar 

  16. Corry, D.B. et al. Decreased allergic lung inflammatory cell egression and increased susceptibility to asphyxiation in MMP2-deficiency. Nat. Immunol. 3, 347–353 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Greenlee, K.J. et al. Proteomic identification of in vivo substrates for matrix metalloproteinases 2 and 9 reveals a mechanism for resolution of inflammation. J. Immunol. 177, 7312–7321 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  19. Wilson, C.L. et al. Regulation of intestinal α-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 286, 113–117 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Gearing, A.J. et al. Matrix metalloproteinases and processing of pro-TNF-α. J. Leukoc. Biol. 57, 774–777 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Corry, D.B. IL-13 in allergy: home at last. Curr. Opin. Immunol. 11, 610–614 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Corry, D.B. et al. Requirements for allergen- induced airway hyperreactivity in T and B cell-deficient mice. Mol. Med. 4, 344–355 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Grunig, G. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–2263 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Denning, T.L., Wang, Y.C., Patel, S.R., Williams, I.R. & Pulendran, B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat. Immunol. 8, 1086–1094 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Mucida, D. et al. Reciprocal Th-17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Connor, M.J. & Smit, M.H. Terminal-group oxidation of retinol by mouse epidermis. Inhibition in vitro and in vivo. Biochem. J. 244, 489–492 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cheung, P.F., Wong, C.K., Ip, W.K. & Lam, C.W. IL-25 regulates the expression of adhesion molecules on eosinophils: mechanism of eosinophilia in allergic inflammation. Allergy 61, 878–885 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Fort, M.M. et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 15, 985–995 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Swee, M., Wilson, C.L., Wang, Y., McGuire, J.K. & Parks, W.C. Matrix metalloproteinase-7 (matrilysin) controls neutrophil egress by generating chemokine gradients. J. Leukoc. Biol. 83, 1404–1412 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Liu, D. et al. Overexpression of matrix metalloproteinase-7 (MMP-7) correlates with tumor proliferation, and a poor prognosis in non-small cell lung cancer. Lung Cancer 58, 384–391 (2007).

    Article  PubMed  Google Scholar 

  32. Ito, T.K., Ishii, G., Chiba, H. & Ochiai, A. The VEGF angiogenic switch of fibroblasts is regulated by MMP-7 from cancer cells. Oncogene 26, 7194–7203 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Upham, J.W. et al. Retinoic acid modulates IL-5 receptor expression and selectively inhibits eosinophil-basophil differentiation of hemopoietic progenitor cells. J. Allergy Clin. Immunol. 109, 307–313 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Takamura, K. et al. Retinoic acid inhibits interleukin-4-induced eotaxin production in a human bronchial epithelial cell line. Am. J. Physiol. Lung Cell. Mol. Physiol. 286, L777–L785 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Takaki, H. et al. STAT6 Inhibits TGF-β1-mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor. J. Biol. Chem. 283, 14955–14962 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. McGowan, S.E., Holmes, A.J. & Smith, J. Retinoic acid reverses the airway hyperresponsiveness but not the parenchymal defect that is associated with vitamin A deficiency. Am. J. Physiol. Lung Cell. Mol. Physiol. 286, L437–L444 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Maret, M. et al. Liposomal retinoic acids modulate asthma manifestations in mice. J. Nutr. 137, 2730–2736 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Schuster, G.U., Kenyon, N.J. & Stephensen, C.B. Vitamin A deficiency decreases and high dietary vitamin A increases disease severity in the mouse model of asthma. J. Immunol. 180, 1834–1842 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Mora, J.R., Iwata, M. & von Andrian, U.H. Vitamin effects on the immune system: vitamins A and D take center stage. Nat. Rev. Immunol. 8, 685–698 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Coombes, J.L. & Powrie, F. Dendritic cells in intestinal immune regulation. Nat. Rev. Immunol. 8, 435–446 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sun, C.-M. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Benson, M.J., Pino-Lagos, K., Rosemblatt, M. & Noelle, R.J. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J. Exp. Med. 204, 1765–1774 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Elias, K.M. et al. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood 111, 1013–1020 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Peters-Golden, M. The alveolar macrophage: the forgotten cell in asthma. Am. J. Respir. Cell Mol. Biol. 31, 3–7 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Careau, E. et al. Antigen sensitization modulates alveolar macrophage functions in an asthma model. Am. J. Physiol. Lung Cell. Mol. Physiol. 290, L871–L879 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Diaz-Sanchez, D., Tsien, A., Fleming, J. & Saxon, A. Combined diesel exhaust particulate and ragweed allergen challenge markedly enhances human in vivo nasal ragweed-specific IgE and skews cytokine production to a T helper cell 2-type pattern. J. Immunol. 158, 2406–2413 (1997).

    CAS  PubMed  Google Scholar 

  47. Grumelli, S. et al. An immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema. PLoS Med. 1, e8 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Montes, M., Jaensson, E.A., Orozco, A.F., Lewis, D.E. & Corry, D.B. A general method for bead-enhanced quantitation by flow cytometry. J. Immunol. Methods 317, 45–55 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank P. Woo Park (Children's Hospital, Harvard School of Medicine) for Mmp7−/− mice backcrossed to C57BL/6 mice; D.A. Engler, R.K. Matsunami and K. Gonzalez for technical help with proteomics analysis; N. Barrows for editorial support; and all members of the Kheradmand and Corry laboratory for comments and criticisms. Supported by the US National Institutes of Health (AI070973 and HL082487 to F.K.; AI071130 and AR050772 to C.D.; and HL075243, AI057696 and AI070973 to D.B.C.), the American Lung Association (C.D.), the Leukemia and Lymphoma Society (C.D.) and MD Anderson Cancer Center (C.D.).

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Authors and Affiliations

  1. Department of Immunology, Baylor College of Medicine, Houston, Texas, USA

    Sangeeta Goswami, Ming Shan, David B Corry & Farrah Kheradmand

  2. Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Pornpimon Angkasekwinai & Chen Dong

  3. Department of Biological Sciences, North Dakota State University, Fargo, North Dakota, USA

    Kendra J Greenlee

  4. Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

    Wade T Barranco, Sumanth Polikepahad, Alexander Seryshev, Li-zhen Song, David B Corry & Farrah Kheradmand

  5. Department of Medicine, University of Texas Medical Branch Galveston, Texas, Galveston, USA

    David Redding, Bhupinder Singh & Sanjiv Sur

  6. Department of Medicine, University of California San Francisco, San Francisco, California, USA

    Prescott Woodruff

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  1. Sangeeta Goswami
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Contributions

S.G. did animal experiments, in vitro cleavage assay, immunohistochemistry, flow cytometry, RT-PCR, ELISA and Luminex assays; P.A. did in vitro T cell experiments; W.T.B. and S.P. did airway physiology experiments; K.J.G. did proteomics analysis; A.S. made liposomal ATRA and helped with HPLC; M.S., L.S., D.R., B.S. and S.S. did the ragweed challenges of humans and ELISA of samples from allergic volunteers; P.W. obtained bronchial biopsies of asthmatic and control volunteers; S.G., F.K., D.B.C. and C.D. designed experiments; S.G. and F.K. wrote the manuscript; and P.A., D.B.C. and C.D. critically reviewed the manuscript.

Corresponding authors

Correspondence to David B Corry or Farrah Kheradmand.

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Goswami, S., Angkasekwinai, P., Shan, M. et al. Divergent functions for airway epithelial matrix metalloproteinase 7 and retinoic acid in experimental asthma. Nat Immunol 10, 496–503 (2009). https://doi.org/10.1038/ni.1719

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