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can be beneficial to neuronal survival at low concentra the nervous system, specifically on neurons, both the
tions. [43,105,54,106] On the other hand, glucose deprivation fields of neurodevelopment and neurodegeneration
increased TLR4 expression and cell death in neuronal have much to explore with regards to TLR8. This TLR
cultures while TLR4 neurons were less susceptible to could be considered critical to study the role of TLRs
-/-
glucose deprivation induced cell death. [29,37] In agreement on neurons in neurodegeneration, and PD in particular.
with the in vivo results, it seems that TLR4 stimulation
per se is not harmful to neurons and it might even be NEURONAL TLRS AND VIRAL INFECTIONS
beneficial. During stroke TLR4 has a negative impact
on neuronal survival, possibly in part through glucose In the previous sections we have discussed that
deprivation, but most likely also as the result of a more TLRs play an important role in microglial-mediated
profound inflammatory process. [107] In relation to the neuroinflammation of neurodegenerative diseases.
opposing effects of TLR4 in PD, it is curious that TLR4 In this context it is extremely relevant to investigate
can have either protective or detrimental effects in the further the TLR-induced immune-like functions of
context of stroke. neurons and to understand the role of neurons in
neuroinflammation. Viral infections offer useful
TLR8 conditions to study TLR-mediated neuronal immune
In innate immune cells TLR8 functions as an functions, because neurons respond to viral infections
endosomal receptor that recognizes viral single- by upregulating TLR and secreting IFN.
stranded RNA. Stimulation of TLR8 induces the Neurons upregulate TLR3 and TLR4 mRNA in
activation of the My88 signaling pathway leading to
an anti-viral response. [108] response to HIV and adenovirus infection, they also
upregulate IFN-β mRNA in response to Sendai virus,
and increase IFN production after TLR3 and TLR8
The role of TLR8 in PD and AD has not yet been studied
in detail, and is therefore unknown. In stroke patients a stimulation. [16,27,45,111] TLR3 and TLR8 are virus-sensing
higher level of TLR8 mRNA expression in whole blood receptors and virus-infected cells use IFNs to signals
sample was positively correlated with poor patient to the neighboring cells that an infection is ongoing
outcome after three months, larger infarct volume and to induce an immune response from nearby
and greater inflammatory response. [109] Similar results immune cells (or glial cells). All together, such findings
were found in a mouse stroke model: diseased animals suggest that neurons can act as immune cells. These
had increased TLR8 mRNA expression in their brain neuronal TLR-mediated immune responses seem to be
and systemic administration of a TLR8 agonist before protective to the neurons themselves. Stimulation of
ischemic insult increased infarct size and neurological TLR3 on neuronal cell lines inhibits HIV replication
problems. [110] The neuronal damage in stroke patients through IFN-λ, and TLR3 and TLR8 stimulation of
a neuronal cell line results in lower susceptibility to
and mice could be mediated by neuronal TLR8, since herpes simplex virus-1 potentially through IFN-α.
TLR8 stimulation of neurons results in fewer and shorter -/-
neurites and apoptosis and slightly but significantly Moreover, TLR3 primary neurons showed increased
infection when exposed to West Nile virus compared to
increases oxygen-glucose deprivation induced cell WT neurons which was not due to changes in IFN-α of
death, while TLR8 silencing reduced oxygen-glucose IFN-β production. [16,45,46] The protective effect of TLR3
deprivation induced cell death. [26,110] Interestingly, during viral infection of the CNS has been confirmed
neurodevelopmental research has shown that TLR8 in mice: infection of TLR3 mice with West Nile virus
-/-
is differentially expressed in the embryonic and resulted in a higher viral burden in neurons and
postnatal brain in mice. [25,26] In the mouse brain TLR8 increased mortality compared to WT mice. The viral-
[46]
expression increases between embryonic day 12 and sensing receptors TLR3 and TLR8 are able to initiate a
postnatal day 1, and decreases between postnatal day 7 protective immune-like response in neurons upon viral
[26]
and adulthood. During early embryonic development challenge. Unfortunately, it is not clear whether TLR2
TLR8 expression is high in postmitotic migrating or TLR4 have a similar potential to protect neurons
cells, but not in the periventricular proliferative against pathogenic (bacterial) attack, and what the
area. During late embryonic development, TLR8 resulting immune response would be. Therefore, it
[26]
was restricted to axonal tracts (including the olfactory is interesting to investigate a wide range of possible
nerve fiber layer, cortical intermediate zone, internal immune-like responses in neuronal cultures exposed
capsule, anterior commissure, fimbria of hippocampus to endogenous and exogenous TLR2 and TLR4 stimuli.
and optic chiasm). Postnatal expression is diffuse
[26]
throughout the brain and located in soma. This CONCLUSION
[26]
indicates a potential role of TLR8 in brain development.
Considering how little is known about its function in This review summarizes the relevance of TLRs in the

Neuroimmunol Neuroinflammation | Volume 3 | Issue 2 | February 15, 2016 33