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Mycobacteria directly induce cytoskeletal rearrangements for macrophage spreading and polarization through TLR2‐dependent PI3K signaling
Author(s) -
Lasunskaia Elena B.,
Campos Maria. N.,
Andrade Marcelle R. M.,
DaMatta Renato A.,
Kipnis Thereza L.,
EinickerLamas Marcelo,
Da Silva Wilmar D.
Publication year - 2006
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0106066
Subject(s) - microbiology and biotechnology , biology , pseudopodia , cytoskeleton , pi3k/akt/mtor pathway , actin cytoskeleton , mapk/erk pathway , tlr2 , signal transduction , rhoa , chemotaxis , integrin , actin , receptor , cell , biochemistry , tlr4
Macrophage migration and adhesion are important for the control of mycobacterial infection and are critically dependent on the reorganization of the cytoskeleton. Mycobacteria elicit rapid morphological changes, such as cell spreading, a process relevant to in vivo changes of macrophage shape during extravasation and migration. In this study, we investigated the BCG mycobacteria‐induced signaling events leading to macrophage cytoskeletal rearrangements employing specific pharmacological inhibitors to suppress distinct kinase pathways known to be elicited by infection. Viable or lysed mycobacteria, as well as purified cell wall lipoprotein p19, TLR2 agonist, induced RAW264.7 cells to extend actin‐rich pseudopods, which impart radial spreading within 3 h, leading later to persistent cell polarization. BCG induced rapid activation of phosphatidylinositol 3‐kinase, PI3K, activation that was recruited to the activated TLR2 receptor. TLR2‐ neutralizing antibody inhibited macrophage spreading and PI3K activation induced by p19. Additionally, BCG induced spreading and polarization of bone marrow‐derived macrophages from TLR2‐ expressing mice in contrast to their TLR2‐knockout counterparts. Neither MEK1/ERK, p38 MAPK, nor NF‐κB activation were important for the early cytoskeletal rearrangements observed, although suppression of these pathways is known to inhibit chemokine secretion by activated macrophages. Β2‐integrins blockade with a corresponding antibody inhibited macrophage spreading and polarization but had no effect on pseudopodia protrusions demonstrating the downstream position of integrin‐mediated adhesion in PI3K‐ dependent signaling pathway leading to the motility phenotype. The obtained data demonstrate that the direct effect of mycobacteria on macrophage shape might be mediated through TLR2‐dependent PI3K activation.