Biomedical Engineering Reference
In-Depth Information
deletion in mice suggests that these proteins may be crucial in type-I interferon
responses to dsRNA viruses in many cell types while TLR recognition plays a more
specialized role in plasmacytoid DCs [88]. Notably, RIG-I and MDA5 are, them-
selves, interferon inducible, and thus susceptible to positive feedback regulation, as
well as upregulation in the context of type-I interferon production by cells of the
innate immune system. A third member of the RIG-I DExD/H-box
helicase family,
LGP2, has been identified that lacks the N-terminal CARD, and may function as a
negative regulator of RIG-I and MDA5 by competing for binding to dsRNA [79,87].
6.5
NF-
B AND THE INNATE RESPONSE TO
PATHOGENS
κ
The recognition of pathogens by PRRs initiates a complex series of events. The first
is the mounting of immediate antimicrobial responses at the cellular level. This is
an effective and evolutionarily conserved function of TLRs, and one in which NF-
B
has an important role. PRR expression in epithelial cells is especially important in
this early response, although it is believed that the variety of PRR expression in
these cell types is somewhat limited. At the mRNA level, multiple TLRs are differ-
entially expressed in epidermis, gut, pulmonary, urinary, and reproductive epithe-
lium. However, in many cases it is thought that both TLR expression and respon-
siveness is tightly controlled in these cells. For example, keratinocytes upregulate
TLRs expression and responsiveness following TGF
κ
exposure [89]; renal epithelial
cells increase expression of TLR2 and TLR4 in response to IFN
α
[90];
and intestinal epithelial cells have been shown to alter TLR expression under inflam-
matory conditions. However, sentinel cells of the innate immune system, particularly
tissue resident dendritic cells and macrophages, express a more complete comple-
ment of PRRs, and thus are likely to bear the largest portion of the burden in the
earliest events of pathogen recognition. The second part of the innate immune
response, which may occur concomitantly with the first, is the elaboration of proin-
flammatory cytokines and chemokines. Aspects of this response, as they pertain to
inflammation, are discussed in detail in
Chapter 8
.
The classical NF-
γ
or TNF
α
B pathway is crucial to the characteristic response that imme-
diately follows TLR ligation.
p65
-/-
/
tnfr1
-/-
mice have increased susceptibility to
bacterial infection, highlighting the role of p65 in innate immune responses and the
initiation of innate immune responses by nonhematopoietic cells [91]. In contrast
to p65-deficient mice, p50-deficient mice do not show any developmental defects,
however, B cells from
p50
-/-
mice do not respond efficiently to LPS, emphasizing
the importance of the classical p50 containing heterodimeric complexes, i.e., p65/p50
and c-Rel/p50, in TLR signaling [92]. TNFR/IKK
κ
double knockouts show a more
pronounced defect in innate immune responses to bacterial infection, only surviving
a few days after birth while the p65/TNFR1 knockouts can survive for many months.
Therefore, while NF-
β
B family members may partially compensate for the loss of
p65 in some aspects of the TLR transcriptional response, there is no compensation
for the loss of IKK
κ
β
[93,94]. Likewise, MEFs from
nemo
-/-
mice do not exhibit
NF-
κ
B activation by LPS or IL-1 [95]. Therefore, TLR-mediated activation of
