title: Transcellular diapedesis is initiated by invasive podosomes.
abstract: Diapedesis is critical for immune system function and inflammatory responses. This occurs by migration of blood leukocytes either directly through individual microvascular endothelial cells (the "transcellular" route) or between them (the "paracellular" route). Mechanisms for transcellular pore formation in endothelium remain unknown. Here we demonstrate that lymphocytes used podosomes and extended "invasive podosomes" to palpate the surface of, and ultimately form transcellular pores through, the endothelium. In lymphocytes, these structures were dependent on Src kinase and the actin regulatory protein WASP; inhibition of podosome formation selectively blocked the transcellular route of diapedesis. In endothelium, membrane fusion events dependent on the SNARE-containing membrane fusion complex and intracellular calcium were required for efficient transcellular pore formation in response to podosomes. These findings provide insights into basic mechanisms for leukocyte trafficking and the functions of podosomes.
authors.affiliation: The CBR Institute for Biomedical Research, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Carman
authors.forename: Peter T
authors.initials: PT
authors.lastname: Sage
authors.forename: Tracey E
authors.initials: TE
authors.lastname: Sciuto
authors.forename: Miguel A
authors.initials: MA
authors.lastname: de la Fuente
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
authors.forename: Hans D
authors.initials: HD
authors.lastname: Ochs
authors.forename: Harold F
authors.initials: HF
authors.lastname: Dvorak
authors.forename: Ann M
authors.initials: AM
authors.lastname: Dvorak
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Springer
mesh_terms: D002196:Capillaries / Q000166:cytology / Q000276:immunology; D002462:Cell Membrane / Q000737:chemistry; D002465:Cell Movement; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology*; D006801:Humans; D007962:Leukocytes / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology* / Q000648:ultrastructure; D008561:Membrane Fusion; D016062:Porosity; D011554:Pseudopodia / Q000502:physiology* / Q000648:ultrastructure; D050600:SNARE Proteins / Q000032:analysis / Q000378:metabolism; D051316:Wiskott-Aldrich Syndrome Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D050600:SNARE Proteins; D051316:Wiskott-Aldrich Syndrome Protein; D019061:src-Family Kinases