Inflammation & Cell Signaling 2014;1: e111.

http://www.smartscitech.com/index.php/ics

REVIEW

Novel Therapeutic Targets in Neuroinflammation and

Neuropathic Pain
Geeta Ramesh

Division of Bacteriology and Parasitology, Tulane National Primate Research Center, Tulane University, 18703 Three Rivers
Road, Covington, LA, USA

Correspondence: Geeta Ramesh

E-mail: gramesh@tulane.edu
Received: March 06, 2014
Published online: June 16, 2014

There is abounding evidence that neuroinflammation plays a major role in the pathogenesis of neurodegeneration
and neuropathic pain. Chemokine-induced recruitment of peripheral immune cells is a central feature in inflammatory
neurodegenerative disorders. Immune cells, glial cells and neurons constitute an integral network that coordinates the
immune response by releasing inflammatory mediators that in turn modulate inflammation, neurodegeneration and
the signal transduction of pain, via interaction with neurotransmitters and their receptors. The chemokine monocyte
chemoattractant protein-1/ chemokine (C-C motif) ligand (MCP-1/CCL2) and its receptor C-C chemokine receptor
(CCR2) play a major role in mediating neuroinflammation and targeting CCL2/CCR2 represents a promising strategy
to limit neuroinflammation-induced neuropathy. In addition, the CCL2/CCR2 axis is also involved in mediating the
pain response. Key cellular signaling events such as phosphorylation and subsequent activation of mitogen activated
protein kinase (MAPK) p38 and its substrate MAPK-activated protein MAPKAP Kinase (MK) MK-2, regulate
neuroinflammation, neuronal survival and synaptic activity. Further, MAPKs such as extracellular signal-regulated
kinases (ERK), c-jun N-terminal kinase (JNK) and p38 play vital roles in mediating the pain signaling cascade and
contribute to the maintenance of peripheral and central neuronal sensitization associated with chronic pain. This
review outlines the rationale for developing therapeutic strategies against CCL2/CCR2 and MAPK signaling networks,
identifying them as novel therapeutic targets for limiting neuroinflammation and neuropathic pain.
Keywords: neuroinflammation; pain signaling; MCP-1/CCL2; CCR2; MAPK p38, MK-2; MAPK activation

Inflammation & Cell Signaling 2014; 1: e111. doi: 10.14800/ics.111; 2014 by Geeta Ramesh.

Monocyte chemoattractant protein-1 (MCP-1/CCL2)
and its receptor CCR2 in neuroinflammation and
neuropathic pain
Chemokines are implicated in many diseases of the
nervous system. Evidence is emerging that chemokines
play a role in the physiology of the nervous system,
including neuronal migration, cell proliferation and
synaptic activity, besides mediating neuroinflammation
through the recruitment of leukocytes by their chemo-
tactic activity. Chemokines and their receptors are among
the key players responsible for communication between
neurons and inflammatory cells, and this cross talk is
crucial for normal neurological functioning. Chemokines
may induce neuronal death directly through the activation
of neuronal chemokine receptors or indirectly through the
activation of microglial killing mechanisms. Evidence of
major roles for chemokines and their receptors in
diseases of the brain is accumulating and this system is a
potential target for treatment of neurodegenerative
diseases [1].
The chemokine MCP-1/CCL2 that attracts monocytes
and T cells [2] plays a major role in the nervous system.
CCL2 has been suggested to trigger firm adhesion of
leukocytes to activated endothelial cells by upregulating

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Neuroinflammation and Pain signaling

integrins on monocytes, as well as influence their regulation of brain inflammation after peripheral
subsequent diapedesis [3]. Besides modulating the ex- endotoxemia [23].
pression of endothelial adhesion molecules, leukocyte
CCL2 also participates in pain regulation by directly
integrins and cytokine production during central nervous
interacting with sensory neurons and indirectly via
system (CNS) inflammation, CCL2 also regulates the
peripheral leukocyte activation in the PNS [24, 25]. More-
permeability of the blood-brain barrier by opening or
over, neuropathic pain induced by nerve injury is not
altering tight junctions [4]. It is one of the main effectors
elicited in CCR2 gene-deficient mice [24]. It is significant
driving post ischemic infiltration of monocytes into the
to note that CCL2 has been seen to be elevated in primary
brain parenchyma [5]. Expression of CCL2 by reactive
sensory neurons after nerve injury, and CCR2 expression
astrocytes has been documented in demyelinating
has been observed in both dorsal root ganglia (DRG)
multiple sclerosis lesions (MS) [6]. CCL2 expression by
sensory neurons and Schwann cells, in injured peripheral
glial cells is involved in directing leukocytes to sites of
nerves [26]. The addition of CCL2 to cultured DRG
axonal injury in the CNS [7]. Brain micro vessels from
neurons triggered the release of calcitonin gene-related
Alzheimers disease (AD) patients show elevated levels
peptide (CGRP), a nociceptor neurotransmitter, from
of CCL2 [8]. The absence of CCL2 protein in mice leads
these cells presumably as a result of increased neuronal
to decreased local macrophage recruitment in ex-
excitation [26]. The role of CGRP in different models of
perimental autoimmune encephalitis (EAE) [9]. CCL2
pain has been well documented [27].
plays a major role in the recruitment of leukocytes into
the subarachnoid space in various types of infectious The upregulation of CCL2 in the sensory neurons,
meningitis [10]. satellite glial cells and Schwann cells of DRG from
rhesus monkeys when incubated with live B. burgdorferi
The chemokine CCL2 is an important mediator in
spirochetes that cause Lyme neuroborreliosis (in which
many neuroinflammatory and neurodegenerative brain
patients present with excruciating pain along the spine
diseases characterized by neuronal degeneration [11, 12, 13].
and limbs due to radiculitis or inflammation in spinal
CCL2 has been found to be upregulated in actively
nerve roots) has been recently reported [28]. Besides
demyelinating MS plaques [14], and its expression is
mediating inflammation in the nerve roots, CCL2
increased in EAE [15]. CCL2 modulates microglial
induced in the cells of the DRG may also be involved in
activation and proliferation, thereby contributing to the
the signaling of the pain response in Lyme neuro-
inflammatory response mounted in the CNS [16]. CCL2 is
borreliosis. A recent study indicates that activation of
known to play a role in mediating nerve damage and
paracrine CCL2/CCR2 signaling between DRG neurons
demyelination of axons by causing an influx of mono-
plays a critical role in the development of peripheral
cytes and T cells in Wallerian degeneration [17]. CCL2
neuropathy associated with Taxol treatment for cancer.
levels are elevated in the cerebrospinal fluid (CSF) of
Blocking CCL2/CCR2 signaling by anti-CCL2 antibody
patients with Lyme neuroborreliosis [18] a disease that
resulted in the prevention of Taxol-induced peripheral
shows similar clinical signs as that shown by MS [19].
neuropathy including mechanical hypersensitivity and
High levels of CCL2 have been found in the CSF and
loss of intra epidermal nerve fibers, suggesting that
localized in the microglia of the spinal cord of rhesus
targeting CCL2/CCR2 signaling could be a novel
monkeys infected intrathecally with Borrelia burgdorferi,
therapeutic approach [29]. CCL2 is derived from several
the spirochete that causes Lyme neuroborreliosis [20], and
types of cells in the peripheral and central nervous
CCL2 may also possibly contribute to the axonal damage
systems following nerve injury, and is largely involved in
that affects patients with Lyme neuroborreliosis of the
the pathogenesis of neuropathic pain [30]. Further studies
peripheral nervous system (PNS) [21].
focussing on the functions of the chemokine-cytokine
The induction of neuronal CCL2 during mild network-mediated regulation of neuroinflammation may
impairment of oxidative metabolism caused by microglial lead to novel therapeutic strate-gies against neuropathic
recruitment/activation exacerbated neurodegeneration in pain.
Thiamine deficiency (TD)-induced neuronal death.
Conversely CCL2-knockout (KO) mice were resistant to
TD-induced neuronal death, suggesting that the The role of MAPK p38 in neuroinflammation,
chemokine CCL2 mediates microglial recruitment and apoptosis and glutamate mediated excitotoxicity
neurodegeneration in this model [22]. Interestingly, CCL2-
The MAPKs are a specific class of serine/threonine
deficient mice showed reduced neuroinflammatory
kinases that respond to extracellular signals such as
responses and increased peripheral inflammatory
growth factors, mitogens and cellular stress and mediate
responses to peripheral endotoxin insult. Collectively,
proliferation, differentiation and cell survival in
these data demonstrate a significant role for CCL2 in

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Neuroinflammation and Pain signaling

mammalian cells. There are distinct groups of MAPKs damaging rather than a protective effect [45]. Prolonged
within mammalian cells including p38 MAPK, ERKs and and sustained activation of glial cells can result in an
JNKs [31]. exaggerated inflammatory response that causes neuronal
cell death through the elevated release of proin-
In the CNS, activation of the p38 MAPK pathway
flammatory cytokines, which have a potential neurotoxic
constitutes a key step in the development of neuroin-
effect leading to neurodegeneration [46, 47]. A role for p38
flammation. Inflammatory stimuli bind to receptors of the
MAPK activation in mediating astrogliosis has also been
cell surface triggering intracellular signal transduction
documented in Lyme neuroborreliosis [48, 49].
pathways such as the nuclear factor (NFkB) pathway and
the MAPK pathways [32, 33]. Intracellular p38 MAP kinase
gets activated and profoundly modulates somatic
The role of p38 MAPK and its substrate MAPK
inflammatory responses. MAPK p38 signaling controls
activated protein MAPKAP Kinase (MK) MK-2 in
the expression of adhesion molecules, cytokines and
neuroinflammation
chemokines, and a variety of other factors that mediate
and control the inflammatory process. Many in- Several p38 MAPK targets are kinases and
flammatory response proteins such as tumor necrosis transcription factors, known to play a role in
factor (TNF-, interleukin (IL-1, interleukin (IL-6), inflammation via the production and activation of
interleukin (IL-8) and CCL2 depend on p38 signaling for inflammatory mediators. It is known that p38 MAPK
their production [34, 35]. The chemokine CCL2 activates becomes activated by many cellular stresses besides
the p38 MAPK pathway in cultured rat hippocampal cells inflammatory cytokines [50, 51]. The identification of
[36]
. IL-1 induction of neuron apoptosis depends on p38
[52]
MAPK activity after spinal cord injury [37]. residues and the discovery of MK2 as being a direct
Apoptosis or cell death following cytokine-mediated
of the possible molecular mechanisms that could be
glutamate-induced excitotoxicity in the brain is also
involved in the activation of p38 MAPK cascades [53, 54].
mediated by p38 MAPK [38]. Pro-inflammatory cytokine
MAPKAP Kinases (MKs), MAPKAPK-2 (MK-2) and
expression and p38 MAPK signaling have been
MAPKAPK-3 (MK-3) are serine/threonine kinases are
implicated in glutamate-induced neuronal death of
part of the subfamily that bind to and are specifically
neonatal rats, and their inhibition may have an important
activated by the p38 MAPK isoforms [55, 56]. MK-2 is
neuroprotective role as part of an anti-inflammatory
recognized as the most important kinase to be activated
therapeutic strategy [38]. Excitotoxic neuronal death
by p38 MAPK since it has a vital role in mediating both
occurs through the activation of N-methyl-D-aspartate
cellular stress and inflammatory responses. The p38
(NMDA) and non-NMDA glutamatergic receptors in the
MAPK/MK-2 complex has been documented to
CNS [39]. Glutamate also induces strong activation of p38
contribute to inflammation in vivo, since MK-2 knockout
and indeed, cell death can be prevented by inhibitors of
mice are resistant to endotoxic shock as a result of
the p38 MAPK pathway. Furthermore, intracellular
lipopolysaccharide (LPS)-stimulation [57]. MK-2 is in-
signals generated by-amino-3-hydroxy-5-methyl-4-
volved in regulating the production of TNF-, IL-6, IL-8,
isoxazolepropionic acid (AMPA) receptors activate the
and several other cytokines that play a role in
stress sensitive MAP kinases implicated in apoptotic
inflammation [58, 59]. MK-2 expression and activation is
neuronal death such as JNK and p38. NMDA and AMPA
increased in microglia that have been stimulated with
receptor expression and cortical neuronal death are
LPS- and interferon-, and microglial cells cultured from
associated with p38 MAPK in glutamate-induced
MK-2 knockout mice showed a reduction in the levels of
excitotoxicity in vivo [39]. Neuronal cell death due to
inflammatory cytokines [60]. This signaling is of particular
glutamate excitotoxicity is mediated by p38 MAPK
interest as the p38 MAPK/MK-2 pathway and the
activation in the rat cerebral cortex [40]. Inhibition of
consequent production of inflammatory cytokines have a
delayed induction of p38 MAPK attenuates kainic
significant role in neurodegenerative disease processes
acid-induced neuronal loss in the hippocampus [41, 42, 43].
where oxidative stress and persistent neuroin- flammation
In addition, MAPK p38 participates in the neuronal MAP
are the primary causes of disease. MAPKAP kinase-2,
kinase cascade of signaling mechanisms that integrate
one of p38 MAPKs more prevalent substrates has also
synaptic plasticity and memory [44].
been implicated in Parkisons disease (PD), where it has
Irregularities in p38 MAPK signaling in neuronal cells been shown that MK2-deficient mice show decreased
have been associated with diseases linked with levels of neuroinflammation and loss of dopaminergic
neuroinflammatory processes where persistent inflamm- neurons within the substantia nigra after treatment with
atory stimuli such as chronic microglial activation have a the Parkinsons inducing neurotoxin 1-methy-4-phenyl-1,

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Neuroinflammation and Pain signaling

2, 3, 6-tetrahydropyridine (MPTP) compared to MK-2 Experimental pain models have shown sustained
wild-type mice [61]. MAPK activation in nociceptive primary sensory neurons
present in the DRG, second order neurons located in the
MAPK p38 and its substrates have been shown to
dorsal horn of the spinal cord, neurons located in the
modulate neuronal plasticity and have been implicated in
brainstem and thalamic-cortical regions that are important
several neurodegenerative diseases. The release of
for nociceptive processing and interpretation of pain
pro-inflammatory cytokines as a result of activation of
related signaling information [72, 73]. Importantly, inhibi-
the p38 MAPK cascade, has been reported to be involved
tion of MAPK phosphorylation, both of ERKs and p38,
in AD, PD, MS, cerebral ischemia, depression and
resulted in the production of antinociceptive activity in
neuropathic pain [62]. The activation of p38 MAPK
experimental pain models [69]. MAPK activation is con-
signaling mediates changes in morphology and density of
sidered to be an essential component of nociceptive
dendritic spines seen during the development of
peripheral and central sensitization and proposed to
neurodegenerative disease and is associated with memory
function as a master switch in the initiation and
impairment after epileptic seizures [62]. The understanding
maintenance of pathological pain. Increased MAPK
of the functional role of the p38 MAPK signaling cascade
phosphorylation (activation) has been observed in
in affecting synaptic plasticity in the hippocampus and its
neurons and glia in peripheral nerve fibers, DRG cells,
potential role in neurodegenerative diseases such as AD
and the spinal cord dorsal horn and supraspinal areas
has made significant progress. Several formulations of
relevant to pain-processing [74]. Studies have indicated
p38 MAPK inhibitors are being actively screened in
that topical application of capsaicin to the hind paw
phase II clinical trials for depression. Evaluation of
results in the increased phospho-p38 (activated) immune-
MAPK p38 inhibitors as therapeutic agents in neural
reactivity in the nerve fibers of the dermis [75]. Further,
diseases is an active area of research and they are being
intraplantar injection of capsaicin induced phosp-
rigorously explored in both preclinical experimental
horylated ERK in intra-epidermal nerve fibers and nerve
models in addition to clinical trials for various
bundles, which was subsequently prevented when
inflammatory diseases [63].
pretreated with MAPK kinase enzyme (MEK) inhibitor
[76]
. Surgical models of neuropathic pain revealed
differential activation of p38, ERK and JNK in neurons
The role of Mitogen activated Protein Kinase (MAPK)
and glia of DRG that were in turn attenuated by using
signaling in the transduction of the pain response
inhibitors that block MAPK phosphorylation [72, 77, 78, 79,
80, 81, 82]
Pain is a feeling of distress caused by activation of .
specific nerve endings in response to various stimuli
MAPK p38 has been the subject of extensive efforts in
capable of causing tissue injury. This specialized sensory
basic research and drug discovery [83]. Inhibition of p38
processing, also defined as nociception leads to a reflex
MAPK and ERK differentially modulates cytokine
or withdrawal response that helps to reduce or prevent
expression [41]. MAPK p38 is a key signaling molecule
tissue injury [64]. However, over time, nociceptive
and a therapeutic target for inflammatory diseases such as
sensitization may take on a detrimental role where
arthritis [32]. A specific inhibitor of p38 MAPK,
increased sensitivity can lead to prolonged activation of
SB203580 (Calbiochem) was effective in affording brain
nociceptors, and the subsequent recruitment of peripheral
protection with a wide therapeutic window against focal
and central mechanisms may result in persistent pain
ischemic insult in rats by suppressing the expression of
perception [65]. There is growing evidence that MAPKs
pro-inflammatory cytokines [84]. Considering the central
such as p38, ERK1/2 and JNK play a critical role in the
role that MAPK signaling, particularly p38 MAPK plays
signal transduction cascade associated with chronic
in orchestrating the immune response, glutamate-
nociception [66, 67]. The activation of MAPKs mediated by
mediated excitotoxic neuronal and glial damage,
inflammatory and stress stimuli, neurotransmitters,
modulation of synaptic function and the signal
growth factors and hormones, mediate diverse intracell-
transduction of the pain response, MAPK signaling
ular responses operative both at the transcriptional and
cascades serve as novel targets for the development of
post-transcriptional levels [68]. Protein kinase p38 MAPK
therapeutic strategies aimed at treating neuroin-
is also a potential target for the treatment of pathological
flammatory diseases that result in neurodegeneration,
pain [69]. Activation of p38 MAPK in spinal microglia is a
demyelination as well as neuropathic pain.
critical link in inflammation-induced spinal pain
processing [70], and its activation in uninjured primary
afferent neurons and in spinal microglia contribute to the
Concluding remarks
development of neuropathic pain induced by selective
motor fiber injury [71].

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Neuroinflammation and Pain signaling
Accumulating evidence suggests that there are major
roles for the chemokine MCP-1/CCL2 and its receptor
CCR2 in inflammatory neurodegenerative disease, in
addition to the signal transduction of the pain response.
The MAPK p38/MK-2 signaling cascade has funda-
mental roles in mediating neuroinflammation, modulating
neuronal and glial survival and apoptosis, particularly via
glutamate mediated excitotoxicity, besides regulating
neuronal plasticity. Although the pathological processes
responsible are not fully understood, there is substantial
evidence that activation of MAPKs is critical to
peripheral and central sensitization associated with
conditions of nociceptive inflammatory and neuropathic
pain. Crosstalk between neurons and glia is an essential
component of pathogenic pain development and
increased MAPK phosphorylation in neurons and glia of
the DRG, spinal cord and cortex is considered to be a
biochemical marker of pain signaling. Nociceptive-
induced cellular signaling in experimental pain models,
specifically MAPK phosphorylation, can be utilized to
provide mechanistic insights into drug-target interaction
along the nociceptive pathways. Together, CCL2/CCR2
and MAPK signaling networks represent novel
therapeutic targets for the development of therapeutic
strategies aimed at limiting neuroinflammation and
neuropathic pain associated with neurological disease
states.
Acknowledgement
The author was supported by grant 51OD011104/
P51RR000164 from the Office of Research Infrastructure
Programs (ORIP) and the National Center for Research
Resources of the National Institutes of Health to the
Tulane National Primate Research Center and by grant
NS048952 from the National Institute of Neurologic
Disorders and Stroke to Mario T. Philipp.
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To cite this article: Geeta Ramesh. Novel Therapeutic Targets in
Neuroinflammation and Neuropathic Pain. Inflamm Cell Signal
2014; 1: e111. doi: 10.14800/ics.111.