Three-dimensional migration of macrophages requires Hck for podosome organization and extracellular matrix proteolysis.
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 barely reached the peritoneal cavity. In vitro, 3-dimensional (3D) migration and matrix degradation abilities, 2 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, as the first protein combining a phagocyte-limited expression with a role in 3D migration, could be a target for new anti-inflammatory and antitumor molecules.
Cougoule
Céline
C
Centre National de la Recherche Scientifique (CNRS), Institut de Pharmacologie et de Biologie Structurale (IPBS), Département Mécanismes Moléculaires des Infections Mycobactériennes, Toulouse, France.
Le Cabec
Véronique
V
Poincloux
Renaud
R
Al Saati
Talal
T
Mège
Jean-Louis
JL
Tabouret
Guillaume
G
Lowell
Clifford A
CA
Laviolette-Malirat
Nathalie
N
Maridonneau-Parini
Isabelle
I
D016475:3T3 Cells; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism*; D021621:Imaging, Three-Dimensional; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010529:Peritoneal Cavity / Q000473:pathology; D010538:Peritonitis / Q000378:metabolism* / Q000473:pathology; D010586:Phagocytes / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D051572:Proto-Oncogene Proteins c-hck / Q000235:genetics / Q000378:metabolism*
D011480:Protease Inhibitors; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck