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nervous system, and especially in neurodegenerative harmful, but the factors determining the outcome are yet
pathologies. Current literature shows that several unknown. It is conceivable that neuronal TLR4 could
neuronal TLRs are involved in the development of the be protective, but the role of microglial TLR4 is still in
nervous system and in neurodegenerative diseases. uncertain. One explanation for the confounding function
Neuronal TLRs are important for NPC proliferation, of TLR4 in PD needs to be sought in the interaction
axonal growth, cell survival and in defense against between TLR4 stimulation and the stimulation of
viral infections. The capacity of TLR-stimulated other receptors. Such interactions are known to occur
neurons to respond as immune-like cells (production for TLR4, in fact neuronal TLR4 interacts with the
of cytokines and induction of apoptosis) is of special transient receptor potential cation channel V1 receptor
interest for neurodegenerative diseases, since to transduce itch signals and possibly to transduce pain
microglial-mediated neuroinflammation is a feature caused by bacterial infections. [55,113] These data open up
of neurodegenerative diseases. These results raise a new scenario of research in PD, particularly using
the question whether neurons are active contributing specific neuronal TLR4 deficient animals, especially if
to neuroinflammatory degenerative process such as this knock-out can be initiated before, during and after
PD. TLR2, TLR3, TLR4 and TLR8 are all important PD initiation, since the beneficial or detrimental effects
for neuronal function and are implicated in PD, AD of TLR4 in stroke seem to be dependent on the timing of
and stroke. This suggests that these TLRs should be TLR4 stimulation in relation to stroke. Similarly, the study
investigated further in PD and other diseases as the of the effects of TLR4 stimulation in neuronal cultures in
first innate immune receptors on neurons. combination with (microglial) immune signals known
to be important in PD pathology represents also another
Neuronal TLR2 has divergent functions in the nervous research direction.
system. It responds to tissue damage during stroke, and
allows neurons to respond to the neuroinflammatory TLR8 influences neuronal growth and survival and
environment of AD pathology. It is interesting is also important for the initiation of the immune
to analyze the involvement of neuronal TLR2 in response during neuronal viral infections. The
neurodegenerative diseases other than stroke and AD. implications for neurodegenerative diseases are
Elucidating the role of neuronal TLR2 in PD is very manifold, since viral infections have been linked to
attractive, since microglial TLR2 has already been PD and a better understanding of the mechanisms
described in PD pathology. [49,73,77,78] We hypothesize underlying neuronal survival could help to reduce
that α-synuclein triggers neuroinflammation through neuronal death. [112] Since so little is known about TLR8,
microglial TLR2, initiating a positive feedback loop by further investigation about the role of this receptor
increasing TLR2 expression on the microglia, resulting represents an opportunity for future PD research.
in neurodegeneration and disease progression. The Neuronal TLRs are an emerging research area, which
contribution of neuronal TLR2 in this process is yet will have implications for neurodevelopmental,
unknown, and could be evaluated by studying PD neurodegenerative and neuroinflammatory research. To
mouse models with a specific knock-out of TLR2 in date neuronal TLR2-4 and neuronal TLR8 are known to
neurons, and by studying the immune response of be promising candidates for future studies. Elucidation
neurons activated with TLR2 stimuli in culture. of the function of other neuronal TLRs requires further
research that would lead to a better understanding of the
Neuronal TLR3 regulates cortical development interaction between the nervous system and the immune
and neurogenesis and is able to initiate immune- system.
like responses in response to viral infections. This
provides an interesting perspective to explore the Financial support and sponsorship
function of neuronal TLR3 in neurodegenerative This review was supported by Utrecht University
diseases, since we hypothesize that neuronal TLR3 Focus & Mass Program Drug Innovation Exploring
will be detrimental in this context, and because viral neuro-immunomodulatory targets for drugs and
infections could cause PD through the development medical food concepts in CNS disorders and chronic
of encephalopathy. [112] Expression patterns of TLR3 inflammatory intestinal diseases.
in brain tissue of early and late PD would shed light Conflicts of interest
on whether TLR3 is indeed an interesting candidate J. Garssen is employee at Nutricia research, Utrecht,
for future PD research, and what role neuronal TLR3 the Netherlands.
might play in disease development.
REFERENCES
TLR4 is a very promising target for future PD research.
The effect of TLR4 during PD can be both beneficial and 1. Hashimoto C, Hudson KL, Anderson KV. The Toll gene of

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