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and IRF7, which leads to recruitment of TNFR-associated factor (TRAF3)
and TRAF6 and activation of mitogen-activate protein kinase (MAPK) and
NF-κB
[14,36]
. Thus TLR9 activates NF-κB and/or IRF7. Some nonhema-
topoietic cells express TLR9, wherein its location determines its ability to
activate NF-κB. For example, TLR9 is expressed in the intestinal epithelial
tissues, where the basolateral TLR9 transmits signals and activates NF-κB
in a canonical manner, while the apical TLR9 induces the accumulation of
ubiquitinated IκB in the cytoplasm and prevents activation of NF-κB
[46]
.
Murine studies have emphasized a role for TLR9 in sensing DNA viruses
such as HSV and in eliciting innate immune responses
[47,48]
. Extracellular
DNA-binding protein HMGB1 secreted from monocytes and DCs and from
necrotic cells elicits TLR9-dependent responses, demonstrating a role for
TLR9 in sensing endogenously derived inducers of immunity
[49]
. Synthetic
ODN ligands, such as CpG ODN for TLR9, have been shown to be potent
adjuvants that enhance immunization procedures against a wide range of
viral, bacterial, and parasitic pathogens and also enhance immunotherapy
against neoplasms
[50-52]
. TLR9 has been also implicated in the develop-
ment of autoimmune diseases such as lupus
[53]
. The contribution of TLR7
and TLR9 to autoimmunity is closely linked to their expression in pDCs and
B cells
[53]
. Putative TLR9 CpG-rich endogenous ligands raise serum levels
of IFN and correlate with both lupus activity and severity
[54-56]
. Crossing
TLR9 knockouts onto the MLR/
lpr
background revealed that TLR9 knock-
outs exhibit accelerated disease progression including pDC and lympho-
cyte expansion and high titers of anti-RNP and IFN-α
[39]
.
430
Although all four intracellular TLR sensors, TLRs 3, 7, 8, and 9, are highly
homologous to each other, some key differences exist, in addition to their
somewhat distinct sensing capabilities
[13,15,16]
. The subcellular local-
ization pattern of TLR3 is different from that of TLRs 7, 8, and 9
[13,15,16]
.
While TLR3 is present in early endosomes even after ligand stimulation,
TLRs 7, 8, and 9 reside in the ER under physiological conditions and are
recruited to late endosomes after ligand stimulation, which is a critical
step for triggering consequent cellular signaling. While TLR3 allosterically
transmits signaling through its interaction with TRIF, TLRs 7, 8, and 9 do so
through MyD88
[13,15,16]
. Furthermore, even though both TLR7 and TLR9
are expressed in the same cell types, i.e., pDCs and B cells, and induce type
I IFN production via similar signaling machinery, TLR9-mediated produc-
tion of IFN is suppressed by TLR7 agonists, suggesting that activation of one
is counteracted by the other
[13,15,16,35]
.
RETINOIC ACID-INDUCIBLE GENE I-LIKE RECEPTORS
The observation that TLR3- or TLR7-deficient animals were able to sense
and produce type I IFN in response to RNA viruses led to the discovery of
three DExD/H box RNA helicases known as RIG-I, melanoma differentia-
tion-associated gene 5 (MDA5), and LGP2
[14,57-59]
. These three sensors
are collectively referred to as RLRs. RIG-I and MDA5, but not LGP2, have
two caspase recruitment domains (CARDs) that play an essential role in
transmitting downstream signals through interactions with IPS-1 (also
called MAVS, Cardif, and VISA)
[14,57,58,60]
. IPS-1 is localized on the mito-
chondria and recruits TRAF3, which activates TRAF family member-associ-
ated NF-κB-binding kinase 1 and IKKε, leading to the phosphorylation and
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