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Blood First Edition Paper, prepublished online November 6, 2009; DOI 10.1182/blood-2009-04-218735. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Cougoule, C. Articles by Maridonneau-Parini, I. PubMed PubMed Citation Articles by Cougoule, C. Articles by Maridonneau-Parini, I. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 28, 2009; accepted October 7, 2009. Three-dimensional migration of macrophages requires Hck for podosome organization and extracellular matrix proteolysis Celine Cougoule1, Veronique Le Cabec2, Renaud Poincloux3, Talal Al Saati4, Jean-Louis Mege5, Guillaume Tabouret1, Clifford A. Lowell6, Nathalie Laviolette-Malirat1 and Isabelle Maridonneau-Parini1,7 1 Institut de Pharmacologie et de Biologie Structurale (IPBS), Department, Toulouse, France; 2 Universite de Toulouse, Toulouse, France; 3 Membrane and Cytoskeleton Dynamics, CNRS UMR144, Paris, France; 4 Plateau technique d'histopathologie experimentale de l'IFR-BMT/150, Toulouse, France; 5 Unite de Recherche sur les Maladies Infectieuses Transmissibles et Emergentes, CNRS UMR6236, Institut Federatif de Recherche 48, Universite de la Mediterranee, Faculte de Medecine, Marseille, France; 6 Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, United States * Corresponding author; email: isabelle.maridonneau-parini{at}ipbs.fr Abstract Tissue infiltration of phagocytes exacerbates several human pathologies including chronic inflammations or cancers. However, the mechanisms involved in macrophage migration through interstitial tissues are poorly understood. We investigated the role of Hck, a Src-family kinase involved in the organization of matrix adhesion and degradation structures called podosomes. In hck-/- mice submitted to peritonitis, we found that macrophages accumulated in interstitial tissues and poorly reached the peritoneal cavity. In vitro, three-dimensional (3D)-migration and matrix degradation abilities, two protease-dependent properties of bone marrow-derived macrophages (BMDMs), were affected in hck-/- BMDMs. These macrophages formed few and undersized podosome rosettes and, consequently, had reduced matrix proteolysis operating underneath despite normal expression and activity of Matrix Metalloproteases. Finally, in fibroblasts unable to infiltrate matrix, ectopic expression of Hck provided the gain of 3D-migration function which correlated positively with formation of podosome rosettes. In conclusion, spatial organization of podosomes as large rosettes, proteolytic degradation of extracellular matrix and 3D-migration appeared to be functionally linked and regulated by Hck in macrophages. Hck being the first protein combining a phagocyte-limited expression to a role in 3D-migration, it could be a target for new anti-inflammatory and anti-tumour molecules. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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