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Proteomic Identification of In Vivo Substrates for Matrix Metalloproteinases 2 and 9 Reveals a Mechanism for Resolution of Inflammation¹

Kendra J. Greenlee^*, David B. Corry^*,, David A. Engler, Risë K. Matsunami, Philippe Tessier^¶, Richard G. Cook, Zena Werb^|| and Farrah Kheradmand^2,*,

^* Department of Medicine and Department of Immunology, Baylor College of Medicine, Houston, TX 77030; Department of Internal Medicine, University of Texas Medical School, Houston, TX 77030; Texas Heart Institute, Houston, TX 77030; ^¶ Infectious Diseases Research Center and Department of Medicine, Laval University, Québec, Canada; and ^|| Department of Anatomy, University of California, San Francisco, CA 94143

Clearance of allergic inflammatory cells from the lung through matrix metalloproteinases (MMPs) is necessary to prevent lethal asphyxiation, but mechanistic insight into this essential homeostatic process is lacking. In this study, we have used a proteomics approach to determine how MMPs promote egression of lung inflammatory cells through the airway. MMP2- and MMP9-dependent cleavage of individual Th2 chemokines modulated their chemotactic activity; however, the net effect of complementing bronchoalveolar lavage fluid of allergen-challenged MMP2^–/–/MMP9^–/– mice with active MMP2 and MMP9 was to markedly enhance its overall chemotactic activity. In the bronchoalveolar fluid of MMP2^–/–/MMP9^–/– allergic mice, we identified several chemotactic molecules that possessed putative MMP2 and MMP9 cleavage sites and were present as higher molecular mass species. In vitro cleavage assays and mass spectroscopy confirmed that three of the identified proteins, Ym1, S100A8, and S100A9, were substrates of MMP2, MMP9, or both. Function-blocking Abs to S100 proteins significantly altered allergic inflammatory cell migration into the alveolar space. Thus, an important effect of MMPs is to differentially modify chemotactic bioactivity through proteolytic processing of proteins present in the airway. These findings provide a molecular mechanism to explain the enhanced clearance of lung inflammatory cells through the airway and reveal a novel approach to target new therapies for asthma.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (R01 HL072419 and K02 HL072062 (to F.K.), R01 HL069585 (to D.B.C.), T32 HL07747 (to K.J.G.), and P01 AI053194 (to Z.W.)), and by funds from the Sandler Family Sustaining Foundation (to Z.W. and D.B.C.). P.T. is a scholar from the Fonds de la Recherche en Santé du Québec.

² Address correspondence and reprint requests to Dr. Farrah Kheradmand, Baylor University College of Medicine, One Baylor Plaza, Suite 520B, Houston, TX 77030. E-mail address: farrahk{at}bcm.tmc.edu

³ Abbreviations used in this paper: MMP, matrix metalloproteinase; BAL, bronchoalveolar lavage; WT, wild type; CAA, complete Aspergillus allergen; PAS, periodic acid-Schiff; 2D, two-dimensional; DIGE, differential in gel electrophoresis; KO, knockout; IS, internal standard; IN, intranasal; IPG, immobilized pH gradient.

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