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Page 28 Benusa et al. Neuroimmunol Neuroinflammation 2020;7:23-39 I http://dx.doi.org/10.20517/2347-8659.2019.28

alignment along the AIS and periodic process ends contacting the AIS [Figure 1A] to microglial processes
completely wrapping around the AIS [Figure 1B] [27,99] . Treatment with anti-inflammatory Didox, a free-
radical scavenger and NF-κB modulator [100-102] , resulted in enhanced AIS structural integrity and reduction
in microglial-AIS contact, indicating that EAE-induced inflammation is the driver for AIS disruption and
enhanced microglial-AIS contact.

Microglial-AIS contact increased prior to and concomitant with changes in AIS structure, although it
does not appear that contact alone drives AIS disruption. In the cuprizone model, demyelination and
inflammation are present in the cortex; however, AISs were spared, suggesting the AIS, unlike the NOR,
is not maintained by myelin presence [27,103] . Interestingly, in the cortex of cuprizone-fed mice, reactive
[27]
microglia also enhanced contact with AISs but AIS structure was preserved . Thus, the consequence of
microglial-AIS contact appears to be stimulus dependent. In other models, microglia are recruited to and
make contact with the initial portion of the axon and soma of hyperexcitable cells [35,36] . Microglial-axonal
contact is activity dependent and results in a protective phenotype, preventing the neuron from excitotoxic
death [35,36] . While live-imaging and physiological experiments have not been performed in MS models,
[27]
analysis of AIS plasticity in EAE revealed structural changes of the AIS, such as decreased length , which
can occur in response to hyperexcitable environments [104-106] . Thus, the nature of microglial-AIS contacts
may be context dependent and could either drive disruption or confer protection. Since the AIS is the
axonal domain where action potentials are generated, this consistent microglial-AIS contact in both health
and disease strongly implicates microglia as a regulator and/or modulator of neuronal function and further
studies are needed to investigate the role of enhanced microglial interactions with the AIS in MS and its
models.

The mechanisms mediating microglial contact with either the NOR or AIS remain undefined; however,
as the molecular architecture is highly conserved between these two axonal segments, it is likely that the
molecular mechanisms involved in associations with either region are similar. The fractalkine receptor
CX3CR1 mediates microglial synaptic pruning and microglial contact with neuronal somatic-dendritic
domains, and was, therefore, a prime candidate for mediating microglial-AIS contact [107-109] . However,
absence of CX3CR1 fractalkine receptors on microglia did not alter contact with the AIS in the healthy
mouse brain, suggesting that microglial-AIS interactions are not mediated through the fractalkine
[45]
receptor . Loss of brevican and versican, specialized extracellular matrix molecules surrounding the AIS,
also did not alter microglial contacts onto the AIS . In an effort to determine if AIS proteins are necessary
[45]
for microglial contact, the AIS master scaffolding protein AnkG was knocked down, which disrupted
AIS protein clustering and significantly reduced the number of microglial-AIS contacts, suggesting that
[45]
molecules normally restricted to the AIS are important for microglial-AIS contact . Thus, some progress
has been made in eliminating candidates that mediate microglial-AIS contact and in determining that
[45]
an intact AIS is important for microglial contact, but these experiments focused on microglial contact
specifically with the AIS.

NEUROINFLAMMATION IN TBI
TBI affects millions of people and is associated with devastating financial and societal costs linked to
the long-term morbidities that develop and persist for years after the initial insult [110-113] . Recent studies
have demonstrated the impact of inflammatory cascades in regulating many of these TBI-mediated
outcomes [114-118] . While astrocytes and infiltrating peripheral monocytes/macrophages do play a role
in TBI-induced neuroinflammation, microglia are thought to be the critical mediators of these TBI-
induced neuroinflammatory processes and, therefore, have been the primary focus of TBI-related
neuroinflammatory investigations. However, as it is difficult to specifically identify resident microglia
from peripheral infiltrating monocytes following TBI, many studies call both populations “microglia” for
simplicity. In the following sections, we do the same unless the population is specifically known to be
infiltrating monocytic in origin.