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[37]
hippocampal neurons after I/R injury. However, expression of TLR3 during neurogenesis, as found in
before suggesting a potential role of TLR2 in the the embryonic brain, is also found in cultured neural
treatment of stroke, clinical studies are needed to progenitor cells (NPCs), making NPCs more sensitive
determine whether TLR2 is viable as a marker or target to TLR3-mediated inhibition of proliferation than
for treatment in stroke. mature neurons. Despite this reported decrease
[58]
in TLR3 expression during neurogenesis, neurons
Animal models show that TLR2 is relevant in do express functional TLR3. In primary neurons,
[24]
relation to stroke, however, they might obscure the TLR3 stimulation inhibits neurite outgrowth and
specific importance of neuronal TLR2 in the context causes irreversible growth cone collapse, without
of glial cells. In order to isolate and study neuronal affecting cell survival. Different results were found
[24]
TLR2 in a stroke model, cultured neurons were in the high TLR3-expressing neuroblastoma cell line
exposed to glucose deprivation, a model of stroke. SK-N-AS, where exposure to a TLR3 ligand resulted
[29]
Increased cell death was found in WT neurons, while in growth inhibition and apoptosis. The difference
[44]
TLR2 neurons were resistant to glucose deprivation in results on cell viability could be due to the use of
-/-
induced cell death. In a neuronal cell line oxygen- different cell types (dorsal root ganglia, NPCs, and
[24]
[58]
glucose deprivation resulted in TLR2 upregulation cell lines [44] ), thus revealing the limits of cell culture
[85]
and in an increase of non-apoptotic cell death. as a model of biological processes.
These in vitro data confirm that stroke can result in
neurodegeneration through the activation of neuronal Although all in vivo data are obtained from early
TLR2, making neuronal TLR2 a potential player in life studies and interpretation of these data in the
brain damage after I/R injury in mice, independent context of neurodegeneration must be done carefully,
from the influence of glial TLR2. extrapolating these results leads to the hypothesis that
stimulation of neuronal TLR3 could be detrimental in
Information on TLR2 in the brain of patients with neurodegenerative diseases, especially in the context
stroke is sorely missing and should be sought in
future research, starting with investigating expression of viral infections. TLR3 is a viral sensing innate
patterns in different brain regions. Also, a major focus immune receptor. It is known that viral infections like
[87]
of research should aim at distinguishing neuronal influenza can cause neurodegeneration and that
[88]
TLR2 from glial TLR2. viruses are linked to neurodegenerative diseases:
specifically hepatitis C virus, Eppstein-Barr virus
TLR3 and human immunodeficiency virus (HIV) have been
TLR3 recognizes double stranded RNA associated with associated with PD. [89-91] The involvement of neuronal
viral infection, and host RNA. Ligand binding induces TLRs during viral infections is discussed in more
the production of anti-viral mediators like the type I detail in a later part of this review.
interferons (IFNs), such as IFN-α and -β production
by leukocytes. These IFNs stimulate macrophages and TLR4
natural killer cells to elicit an anti-viral response. [86] TLR4 detects LPS derived from Gram-negative bacteria
and host-derived signaling molecules such as heat
TLR3 has not been studied in direct relationship shock proteins, and extracellular matrix proteins,
to neurodegenerative diseases, but work has been after which the innate immune system is activated,
performed on the effect of TLR3 in the development leading to an inflammatory response. [92-94]
of the nervous system. TLR3 expression decreases
[58]
in the embryonic CNS during neurogenesis. PD
Intrathecal injection of TLR3 agonist polyinosine: The expression of TLR4 is increased in PD and MSA
polycytidylic acid in postnatal day 4 mice resulted post-mortem brain tissue, suggesting clinical relevance
in sensory-motor deficits, neuroanatomical defects to TLR4 in PD and neurodegeneration in general. [50,74]
and fewer axons in the spinal cord, which was Animal experiments have been used to further
-/-
associated with neurodegeneration. The role for elucidate the role of TLR4 in PD. TLR4 mice were more
[24]
TLR3 in this study was demonstrated by the fact that vulnerable to dopaminergic neuronal loss and motor
no anatomical or behavioral problems were found in problems induced by α-synuclein overexpression, but
-/-
TLR3 mice treated with polyinosine: polycytidylic less vulnerable to the induction of PD symptoms by
acid. It seems that TLR3 is involved in the proper 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
[24]
development of the CNS in early fetal life, because treatment. [95,96] Furthermore, TLR4 and α-synuclein
the receptor is differentially expressed at different are both necessary for LPS-induced neurodegeneration
embryonic stages. After birth, stimulation of TLR3 in mice. [97,98] Therefore, mouse models support the
results in neurodegeneration. The decrease in importance of TLR4 in PD, but make no suggestion

Neuroimmunol Neuroinflammation | Volume 3 | Issue 2 | February 15, 2016 31