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residues bind at the interface of the two TLR4 molecules, further strengthen-
ing the interaction. The conformational change in the complex is thought to
promote the recruitment of effector proteins to the intracellular TIR domain
to activate signaling.
Two signaling pathways lead to induction of immunomodulatory cytokines
(reviewed in
Kawai and Akira, 2010
;
Szabo et al., 2010
). On binding LPS, TLR4
activates the MAL-MyD88 pathway, leading to a downstream signaling cascade
resulting in activation of NF-κB and transcription of genes encoding proinflam-
matory cytokines like TNF-α and IL-1β. TLR4 also activates the TRAM-TRIF-
dependent pathway, promoting sustained NF-κB activation and transcription of
genes encoding immunomodulatory cytokines like IL-6 and RANTES.
LPS can bind directly to the TLR4-MD2 complex, or the interaction can be
mediated by lipopolysaccharide binding protein (LBP) and CD14. LBP was
discovered 25 years ago as a serum protein that binds LPS, although we now
know it also binds other microbial components (
Schumann, 2011
). Experiments
in mice have shown that LBP is essential for combating infections. LBP is pri-
marily secreted by the liver, but can also be secreted by epithelial cells in the
lungs, gastrointestinal tract, kidneys, and urinary tract. Upon binding to LPS
in the bloodstream, LBP forms a stable complex with CD14, a receptor that
can be anchored in the membrane of leukocytes or secreted into the blood in a
soluble form (
Thomas et al., 2002
). The complex then mediates transfer of the
LPS molecule to TLR4-MD2, starting a signaling cascade. The formation of the
LBP-CD14-LPS complex allows the body to respond to LPS concentrations as
low as 10 pg/mL (
Thomas et al., 2002
).
In addition to stimulation of the immune system through induction of proin-
flammatory cytokines, LPS also causes an increase in the permeability of epi-
thelial and endothelial cells through a number of mechanisms which have yet to
be fully characterized (
Moriez et al., 2005
;
Sheth et al., 2007
;
Vandenbroucke
et al., 2008
;
He et al., 2011
). The permeability barrier is maintained through the
action of tight junctions, multiprotein complexes that bridge adjacent cells. In
response to LPS, many of the predominant tight junction proteins are redistrib-
uted, leading to the breakdown of tight junctions and increased permeability
(
Sheth et al., 2007
;
He et al., 2011
). This is dependent on TLR4 signaling and
phosphorylation of a number of signaling proteins, like c-Src and myosin light
chain kinase (
Moriez et al., 2005
;
Sheth et al., 2007
). The breakdown of tight
junctions is enhanced by rearrangement of actin filaments through the action
of RhoA and NF-κB (
Vandenbroucke et al., 2008
;
He et al., 2011
). This causes
contraction of the cell and further permeability of the barrier. Disruption of the
barrier allows cells of the immune system to migrate to areas of infection, but
also provides a portal for bacterial translocation, contributing to sepsis.
Dendritic cells (DCs) are potent antigen-presenting cells which link innate
and adaptive immunity. DCs which are positive for DC-specific intracellular
adhesion molecule 3 (ICAM-3)-grabbing non-integrin (DC-SIGN; CD209),
which is a C-type lectin, bind primarily to mannose- and fucose-containing
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