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Benusa et al. Neuroimmunol Neuroinflammation 2020;7:23-39 I http://dx.doi.org/10.20517/2347-8659.2019.28 Page 33

these AXIS microglia could represent a distinct subtype of MPD microglia [45,50] . The interaction between the
AXIS microglia and the AIS appears to be ankrin-G and GABA mediated, while the fractalkine receptor,
[45]
CX3CR1, does not appear necessary for the AXIS microglial interactions .
There are reports indicating that microglia physically interact with injured axons following TBI in the
human brain. In 2014, a study demonstrated co-labeling of microglia with injured proximal axonal
swellings in brains of veterans who had histories of blast injury exposure [181] . Another study showed
potential PC microglia contacting injured axonal swellings when employing double-labeling techniques in
human TBI tissue [182] . These studies indicate that microglial processes may contact axonal swellings in the
human brain following TBI; however, further investigation is needed to comprehensively assess potential
alterations in microglial-neuronal physical interactions in the human population and address how those
changes compare to those observed pre-clinically.

Additionally, a study investigating the expression of neuronal outgrowth marker, GAP43, in injured axonal
segments as it related to the density of microglia in brain tissue from people diagnosed with MS or TBI
demonstrated a positive correlation between neuronal regeneration and microglial density following
TBI in clinical samples [Figure 1C] [183] . Other studies have also observed GAP43 expression in proximal
axonal swellings following injury in both human tissue and following induction of TBI in pre-clinical
models [184-186] . Ultrastructural assessments further demonstrated morphological alterations indicative of
active axonal sprouting of proximal axonal swellings following TBI, demonstrating that axonal process
outgrowth following TBI is possible and potentially likely [Figure 2] [184,185] . Microglia have been shown
to express neurotrophic factors, such as nerve growth factor, following TBI, supporting a potential role
for MPC in post-injury axonal outgrowth [187] . Microglia may also release exosomes that induce neurite
[19]
outgrowth . The role of MPC and/or MPD in potential post-injury axonal sprouting, however, remains
speculative.

CONCLUSION
It is well accepted that microglia mediate neuroinflammatory processes in health and disease via pro-
and anti-inflammatory cytokines and chemokines. However, microglia also appear to mediate neuronal
function through physical contacts onto various neuronal segments, including dendrites, synapses, cells
bodies, and axons. While the study of microglial-axonal contacts is still in its infancy, there are indications
that these contacts play diverse and important roles during normal development and in the healthy
CNS as well as following TBI or in disease states, such as MS. Analysis of microglia in experimental and
human tissues demonstrate that microglia exhibit a spectrum of morphologies including ramified, rod-
like, hypertrophied, and ameboid that all exert unique contact subtypes onto axonal segments indicative
of the diverse roles microglial-axonal interactions play. Microglia and infiltrating monocytes contact
various axonal segments in unique and specific ways that appear tied to the axonal region contacted,
the morphology of the microglia, and the disease state. Further, it appears that the presence of microglia
contacts at axonal domains may confer protection. Some of the immediate questions for this burgeoning
field focus on the potential ameliorative effects of microglial contacts onto axonal and other neuronal
segments as well as the timing of these interactions following various pathologies. Future examinations of
axonal interactions using functional assessments and live imaging techniques could refine the distinction
between axonal contacts of resident microglia and those formed by peripheral monocyte-derived
infiltrating macrophages and help elucidate the nature of these interactions. Furthermore, identifying the
molecules mediating contact between microglia and the axon will point toward new strategies to treat
disease and promote repair in diverse inflammatory pathologies. The studies reviewed herein underscore
the importance of microglial-axonal contacts in the regulation of neural signaling and the need for further
investigation into these variable interactions in both the healthy and injured CNS.