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of opioids exposure, ischemia/stroke, viral infections TLR expression has also been found in several
and Alzheimer’s disease (AD), [28,29,37-43] via GSK3β and neuronal cell lines. The teratocarcinoma derived
JNK. [28,29] TLR3 and TLR8 negatively regulate neuronal human post-mitotic dopaminergic neuronal cell line
development and axonal growth and are involved in NT2-N expresses TLR3. [9,59-61] TLR3 is also expressed
fighting viral infections, [9,16,24,25,27,44-46] through PI3K by human neuroblastoma cell lines (including
pathway. Other information also indicates a role for noradrenergic cell lines, CHP-212 and SK-NSH; a
[27]
TLRs in the nervous system during disease. TLR1-5, noradrenergic and gamma-aminobutyric cell line, SH-
TLR8 and TLR9 are overexpreesed in PD and multiple SY5Y; SH-SY5Y and a noradrenergic and dopaminergic
systems atrophy (MSA) patients and in animal models cell line, BE(2)-C) and primary human neuroblastic
of PD, AD, MSA and amyotrophic lateral sclerosis. [47-53] cells. [27,44,45,59] The rat neuroblastoma cell line B103
[38]
Of these receptors, TLR2 and TLR4 are of special expresses TLR2. The expression of TLR1-9 has been
interest in PD, as will become clear in the sections reported in the human CHP-212 neuroblastoma cell
[16]
dedicated to these TLRs. The current knowledge line. Although cell lines are further removed from
about TLR2 and TLR4 in PD has focused heavily their original biological environment than primary
on microglia, and not so much on neuronal TLRs. cells, they do offer a more readily available source of
To better understand the potential importance of material for further research towards understanding
neuronal TLRs in neurodegeneration and specifically the functions of neuronal TLRs.
in PD, AD and stroke the current knowledge about the
function of neuronal TLRs in neuronal development Glial TLR expression
and neurodegenerative diseases will be discussed here. The importance of glial TLRs in neurodegeneration
is indisputable. [19,32,53,62-65] Glial cells come in many
NERVOUS SYSTEM TLR EXPRESSION shapes and sizes, and have a critical role in the CNS
and PNS, such as immune surveillance, the regulation
This section will cover the expression of TLRs on of chemical environment and the production of
neurons and glial cells [Figure 3]. To discuss the the myelin sheath, which makes them biologically
function of TLRs on neurons it is important to know relevant to the functioning of neurons.
whether neurons express TLRs. For the convenience
of the reader, the information about expression has Glial cells are a heterogeneous group of cells all of
been organized based on location in the nervous them expressing TLRs. Microglia act as immune
system, and stage of life. To discuss the function of surveillance of the CNS and express TLR1-9 in
TLRs in the nervous system it is also necessary to first both humans and mice. [19,20] Astrocytes regulate the
address whether glial cells express TLRs, because of chemical environment of neurons, and they express
their biological relevance for the functioning of the TLR1-9 in mice and TLR1, TLR3-5 and TLR9 in
CNS and PNS. humans, while TLR2 and TLR6-8 were not detected
in human astrocytes. [17,18] Oligodendrocytes and
Neuronal TLR expression Schwann cells respectively produce the myelin sheath
TLR expression on primary neurons has been found in around neuronal axons in the CNS and PNS. Schwann
several species, amongst which are humans, [10,12,13,15,16,45] cells express TLR1-9 in mice, [14,66] while only TLR2
[67]
mice, [13,14,26,28,43,54,55] and rats. [10,27,56,57] Neuronal TLRs has been studied and detected in humans, whereas
are present in both parts of the nervous system; TLR4 has been studied and detected in rats. [68,69]
the CNS [12,26,28] and the PNS. [10,13,14,43,54,57] Expression Human oligodendrocytes only express TLR2 and
[20]
of TLRs by neurons has been confirmed at mRNA TLR3, while TLR1 and TLR4-9 were undetectable.
level, [14,21,24,28,43] and protein level. [10,13,24,26,28,43,54,57,58] Most In glial cells of the enteric nervous system TLR2 -9
[13,22,70]
results on neuronal TLRs come from experiments in have been found, while TLR1 is absent.
embryonic neurons because these are easier to culture NEURONAL TLR FUNCTIONALITY
than neurons from adult animals. Nonetheless,
neurons express TLRs throughout life, starting at Here we provide a comprehensive overview of the
the embryonic stage, [14,24,26,28,43,58] followed by the current knowledge about TLR functionality in the
postnatal, and the young stages, [10,56] and finally in nervous system in relation to neurodegeneration.
[54]
the adult stage of life. [10,12,13,21,58,55,57] Taken together, Specific information about neurons, microglia, and
these data offer many opportunities to study neuronal other cell types is included when appropriate.
TLRs for a wide range of research questions, since
it is reported that TLRs are expressed throughout TLR2
the nervous system and throughout the lifespan of TLR2 is a TLR family member that is able to recognize
animals. bacterial lipopolypeptides and peptidoglycans.

Neuroimmunol Neuroinflammation | Volume 3 | Issue 2 | February 15, 2016 29