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Page 26 Benusa et al. Neuroimmunol Neuroinflammation 2020;7:23-39 I http://dx.doi.org/10.20517/2347-8659.2019.28

NEUROINFLAMMATION IN MS
MS is an autoimmune-mediated disease of the CNS that is characterized by inflammation and
demyelination. While the cause of MS is not fully understood, it is accepted that neuroinflammation,
resulting from the accumulation and activation of macrophages (derived from microglia or infiltrating
monocytes) in the human CNS, is a crucial step in MS pathogenesis, which culminates in injury to
myelin and axons and disrupts the flow of information [53-56] . The autoimmune nature of MS and the role of
[57]
autoreactive peripheral T cells is highly complex and has been reviewed previously . Therefore, we do not
discuss the autoreactive peripheral immune cells in this review. Furthermore, destruction of myelin and
axons, as well as oligodendrocyte cell-death, are directly related to the numbers of activated inflammatory
cells [53,58-60] . The symptoms of MS range widely based on the CNS region affected and include a variety of
motor or sensory dysfunctions such as muscle weakness, spasticity, tremor, unexplained pain or numbness,
[61]
vision problems, and cognitive deficits . While demyelination is a hallmark of MS, axonal injury is also a
prominent pathological feature and is a major contributor of chronic disability in patients [59,60,62-64] . The types
+
+
of axonal injuries in MS and its models include the formation of axonal swellings, reduced levels of Na /K
ATPase, synaptic damage, axon transection, and disruption of axonal domains, such as the node of Ranvier
(NOR) and the AIS [65-69] . These axonal injuries may occur as either a consequence of demyelination [65,70]
or as a primary event, independent of myelin loss [27,71] , although the mechanisms driving primary axonal
pathology are not fully understood. It is appreciated that soluble factors produced by resident microglia
and infiltrating monocytes and their interactions with peripheral immune cells play a pivotal role in driving
axonal injury [59,60,72-75] ; however, recent studies have implicated a mechanistic role for microglia/monocytes
through physical interactions with axonal domains [6,27,28] .

Studies investigating axonal contact by microglia and/or infiltrating monocytes have utilized two common
[27]
models of MS: a toxin-induced demyelinating model, cuprizone , and an immune-mediated model,
experimental autoimmune/allergic encephalomyelitis (EAE) [6,27] . In the cuprizone model, a copper-
chelating toxin, cuprizone, is administered through chow resulting in oligodendrocyte cell death and,
[75]
consequently, loss of myelin . Demyelination is detectable 1-2 weeks after cuprizone treatment with
peak demyelination occurring by 5-6 weeks of exposure [76-78] . The cuprizone model yields substantial
demyelination and, upon removal of toxin-containing chow, spontaneous remyelination occurs. While
this model does not recapitulate immune-mediated aspects of MS, it does allow for the investigation of
fundamental mechanistic questions of the demyelination/remyelination process and roles of myelin in
[75]
the stability of axonal domains . The EAE model is an immune-mediated model that is induced through
subcutaneous injection of myelin proteins accompanied by pertussis toxin and an adjuvant to ignite an
inflammatory response [75,79,80] . The resulting neuroinflammation recapitulates key pathological features
of MS such as inflammation, demyelination, and neuronal insults [75,80,81] . These two models allow for the
rigorous assessment of MS-associated alterations in microglial-axonal interaction due to demyelination
both in the presence of and independent from the autoreactive inflammatory response.

MICROGLIAL CONTACT WITH THE NOR IN MODELS OF MS
[82]
Axonal function requires maintenance of the NOR , and a major regulator of nodal axonal domain
stability is myelin integrity [77,83-89] . For example, cuprizone-induced demyelination resulted in loss of nodal
[77]
and paranodal clustered proteins . Other studies have also demonstrated loss of nodal protein clustering
as a downstream consequence of demyelination in mouse models of MS and postmortem MS tissue [67,69,90,91] .
In addition to NOR disruption, analyses of human MS tissues have revealed that prominent microglia/
macrophage accumulation correlates with active demyelination [56,59,60,67] . Indeed, myelin is required for NOR
stability; however, NOR protein clustering can also be disrupted independent of demyelination. Howell et al.
[67]
used immunohistochemical techniques to study NOR integrity in normal-appearing white matter of MS cases
and in EAE and found NOR disruption correlated with local microglial inflammation but was independent
of demyelinating lesions and did not correlate with the density of infiltrating lymphocytes. This was