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to the pattern recognition receptors [Figure 1]. They
can recognize both small molecular motifs conserved
across microbes (pathogen-associated molecular
pattern or PAMP) [Figure 2], and endogenous molecules
generated during inflammation or tissue damage
(damage associated molecular pattern or DAMP). [2-5]
TLRs can initiate an acute inflammatory reaction
and subsequently can coordinate the activation of the
adaptive immune system. To date, thirteen TLRs are
known, of which ten (TLR1-10) have been described
[6]
in humans. The cell surface TLRs recognize PAMPs
that are mainly constituent of the bacterial cell wall
or are expressed on the bacterial cell surface, such as Figure 1: Toll like receptors are part of the innate immune system and belong
lipopeptides and peptidoglycal (TLR1/TLR2, TLR2/ to the pattern recognition receptors
TLR6, TLR2/TLR10), lipopolysaccharide (LPS) (TLR4)
and flagellin (TLR5). In contrast, the intracellular
TLRs mainly recognize microbial nucleic acid
including viral double-strand RNAs (TLR3), single-
strand RNAs (TLR7 and TLR8) and CpG ODN (TLR9). [7]
TLRs can employ two second messenger pathways;
the myeloid differentiation primary response gene
88 (MyD88) pathway, activating nuclear factor κ-light-
chain-enhancer of activated B cells (NF-κB), or the TIR-
domain-containing adapter-inducing interferon-β
(TRIF) pathway, activating interferon regulatory factor
3 (IRF3) [Figure 2]. NF-κB controls DNA transcription
resulting in the production of pro-inflammatory
cytokines such as tumor necrosis factor α (TNFα),
interleukin (IL)1β and IL6. [7,8] IRF3 is an interferon
(IFN) regulatory factor leading to the production of Figure 2: Different pathogens activate different TLRs. TLRs signal through
two different pathways using myeloid differentiation primary response gene
antiviral type I IFN. [2,7] 88 (MyD88) and TIR-domain-containing adapter-inducing interferon β, leading
to activation of NF-kB and IRF respectively NF-kB leads to DNA transcription
and cytokine production, while IRF leads to interferon production. TLRs: toll
The presence of TLRs on immune cells and epithelial like receptors; NF-kB: nuclear factor κ-light-chain-enhancer of activated B
cells; IRF: interferon regulatory factor
cells is well known, but their expression is not restricted
to these cell types. Glial cells and neurons express
TLRs in both the peripheral nervous system (PNS) and
the central nervous system (CNS) [Figure 3], allowing
neurons to act as immune cells. [9-15] More specifically,
in the CNS neurons, astrocytes and microglial cells
express TLR1-9, whereas oligodendrocytes express
only TLR2 and TLR3. [16-20] Peripheral neurons also
express TLR1-9 and enteric glial cell express TLR1-
5, TLR7 and TLR9. [13,14,21-23] Neuronal TLR signaling
pathways do not necessarily employ NF-κB [24-26] and
may involve the glycogen synthase kinase 3β (GSK3β),
jun-N-terminal kinase (JNK) and phosphatidylinositol
3-kinase/protein kinase B (PI3K/AKT) pathways. [27-29]
Interaction between neurons and the immune
system has already been reported, setting the scene
for neurons acting as immune cells. [30-34] It has been
reported that neuronal TLRs are involved in the
development and homeostasis of the nervous system,
and notably in several neurodegenerative diseases. [35,36]
Both TLR2 and TLR4 are involved in neuronal Figure 3: TLRs are differentially expressed by neurons and glial cells of the
apoptosis, development and survival in the context central, peripheral and enteric nervous system. TLRs: toll like receptors

28 Neuroimmunol Neuroinflammation | Volume 3 | Issue 2 | February 15, 2016