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Page 30 Benusa et al. Neuroimmunol Neuroinflammation 2020;7:23-39 I http://dx.doi.org/10.20517/2347-8659.2019.28

does not result in enhanced post-injury neurodegeneration, indicating that the peripheral inflammatory
response, more than direct microglial activation, precipitates proinflammation-mediated secondary
insults [134,151] . Overall, these studies underscore the intricacies of TBI-induced microglial activation and our
limited understanding of microglial-neuronal interactions following brain injury.

PHAGOCYTOSIS FOLLOWING TBI
One of the most well-studied physical interactions between microglia and neuronal segments following
TBI is phagocytic engulfment. As in the non-injured brain, activated microglia serve a prominent and vital
role in the clearance of cellular debris following brain injury. Upon the initial TBI insult, a multitude of
cellular pathologies progress. One of the most well studied pathologies, and the hallmark of diffuse brain
injury following TBI, is diffuse axonal injury/traumatic axonal injury [125,152-156] . Axonal injury first manifests
as disruption of molecular transport anterogradely down the axon and progresses over hours, days, and
months following injury to a disconnection at the point of initial transport disruption, resulting in a
proximal axonal segment that remains connected to the neuronal cell body and a distal axonal segment
that undergoes Wallerian degeneration [157-159] . Phagocytosis by activated microglia is required to engulf
and clear away the axonal and myelin debris from the Wallerian degeneration of the distal axonal segment
and involves the toll-like receptors, TREM-2, complement receptors 3 and 4, as well as MAC-2, for the
engulfment of myelin, and the purinergic receptor P2RY6 [Figure 1C] [160,161] . Ultrastructural assessments
of the injured brain have demonstrated significant phagocytosis of Wallerian debris by activated microglia
following TBI [52,116,162] . Microglia with ameboid morphologies, indicative of phagocytic activity, were
found primarily in proximity to the distal axonal segment sustaining dieback, but not the proximal axonal
segments, following TBI-induced optic nerve damage [163] . Further, expression of mRNA indicative of
phagocytic activity is significantly increased following trauma [150] . It should be noted, however, that both
microglia and astrocytes containing phagocytic material have been observed, demonstrating that, while
microglia may be the primary phagocytic cells in the brain, astrocytes also phagocytosis debris following
injury [162] . Additionally, not all activated microglia were observed to be phagocytic following TBI, indicating
that phagocytosis is not the only microglial-axonal interaction upregulated following TBI [116] .

ROD MICROGLIA AND TBI
The readily identifiable, yet mysterious, “rod microglia” have been noted following TBI in a variety of pre-
clinical models and in the human population. This subset of microglia appear following injury and are
defined exclusively by their rod-like morphology and chain-like associations that form long microglial
trains of several rod microglia lined up end-to-end [Figure 1C] [164] . These rod-shaped microglia have been
described following a variety of neurological diseases, including neurosyphilis, and appear to be both non-
phagocytic and reversible [165] . Both rod microglia and microglial trains appear primarily in brain regions
in which the fiber tracks are linear, such as the neocortex, brainstem, and hippocampus [124,166-168] . This
subset of rod microglia, however, appear to be absent in areas that are not linearly arranged, such as the
thalamus [166] . The formation of microglial trains appears to be associated with p38; however the function
of these microglial trains remains unknown [169] . Recently, it was found that microglial trains formed by
rod microglia align with the apical dendrite, but not the axon as was previously thought, of pyramidal
neurons in the rodent cortex [Figure 1C] and spatially associate with astrocytes, indicating that this subset
of microglial-neuronal interaction is neuronal-segment specific and could be involved in an additional
interplay between neuroinflammatory cell types [150] . However, the study of rod microglia following TBI is
still in its infancy and requires further investigation into the timing and function of this microglial-axonal
interaction subtype.

TBI-INDUCED PROCESS CONVERGING AND DIVERGING MICROGLIA
Over the last several years, another subtype of microglial-neuronal interaction has been observed following
brain injury. This interaction subtype manifests as physical contacts between activated microglia and