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¹ Division of Cell Biology and Immunology, Wellcome Trust Biocentre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK
² Department of Biochemistry, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Pokfulam, Hong Kong
³ Institute of Biochemistry, Christian Albrecht University, 24098 Kiel, Germany

Correspondence to Colin Watts: c.watts{at}dundee.ac.uk

Toll-like receptor (TLR) signaling induces a rapid reorganization of the actin cytoskeleton in cultured mouse dendritic cells (DC), leading to enhanced antigen endocytosis and a concomitant loss of filamentous actin–rich podosomes. We show that as podosomes are lost, TLR signaling induces prominent focal contacts and a transient reduction in DC migratory capacity in vitro. We further show that podosomes in mouse DC are foci of pronounced gelatinase activity, dependent on the enzyme membrane type I matrix metalloprotease (MT1-MMP), and that DC transiently lose the ability to degrade the extracellular matrix after TLR signaling. Surprisingly, MMP inhibitors block TLR signaling–induced podosome disassembly, although stimulated endocytosis is unaffected, which demonstrates that the two phenomena are not obligatorily coupled. Podosome disassembly caused by TLR signaling occurs normally in DC lacking MT1-MMP, and instead requires the tumor necrosis factor –converting enzyme ADAM17 (a disintegrin and metalloprotease 17), which demonstrates a novel role for this "sheddase" in regulating an actin-based structure.

Abbreviations used in this paper: ADAM17, a disintegrin and metalloprotease 17; BMDC, bone marrow DC; CFSE, carboxyfluorescein succinimidyl ester; DC, dendritic cells; LPS, lipopolysaccharide; MHC, major histocompatibility complex; MMP, matrix metalloprotease; MT1-MMP, membrane type I MMP; PGE₂, prostaglandin E₂; SDC, spleen DC; TLR, Toll-like receptor; TNF-, tumor necrosis factor ; WASp, Wiskott-Aldrich syndrome protein; WIP, WASp-interacting protein.

© 2008 West et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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