Page 29 - Read Online

Benusa et al. Neuroimmunol Neuroinflammation 2020;7:23-39 I http://dx.doi.org/10.20517/2347-8659.2019.28 Page 25

A

B

C

Figure 1. Schematic representation of microglial process contacts in health and disease. Illustration demonstrating various microglial
and monocytic contacts onto axonal segments. A: in the healthy brain, resident microglia (green) contact the neuronal cell body and
axon initial segment. These microglia potentially express TNF-a and CSF1 and are involved in reduction of hyperexcitability in neurons.
The dynamic surveying processes of non-activated ramified microglia also contact various areas of the axon in the healthy CNS. During
development, contacts by resident microglia are involved in pre- and postsynaptic pruning; B: in MS, both resident microglia (green)
and infiltrating peripheral monocytes (red) contact the nodes of Ranvier. Note that the processes of monocytes are found between the
layers of myelin and the axon sheath, while the resident microglial processes are primarily in contact with adjacent monocytes and/or
involved in debris clearance. Neuroinflammatory cells that have yet to be identified as either resident microglia or infiltrating monocytes
(teal) that express TNF-a, INOS, Nox2, and higher levels of activated calpain, wrap the axon initial segment. This wrapping is involved in
a notable reduction in the length of the axon initial segment; C: following TBI, macrophages (monocytes and/or microglia) phagocytosis
the Wallerian debris from the degenerating distal axonal segments of an injured axons. Potential hyperexcitability of neurons following
TBI induces microglial process convergence onto the neuronal soma via elevated ATP levels and/or glutamate levels. Rod microglia (green)
are also common along the apical dendrite following injury; however, their function is currently unknown. Microglial process convergence
onto the proximal injured axonal segment is associated with P2Y12 and potentially confers neuroprotective effects on the damaged axon
leading to axonal sprouting. CNS: central nervous system; MS: multiple sclerosis; TBI: traumatic brain injury; TNF: tumor necrosis factor;
CSF1: colony stimulating factor 1; INOS: inducible nitric oxide synthase; Nox2: NADPH oxidase 2

[45]
strongly suggesting that microglia play a role in regulating AIS structure and function . Additionally,
when repeated stimulations were used to induce neuronal hyperexcitability, microglia extended their
[35]
processes and wrapped around axons . This induced a rapid repolarization in the neuron back to resting
[35]
levels which was lost when microglia were pharmacologically blocked .

Neuroinflammatory microglial changes are associated with various pathologies, including, but not limited
to, spinal cord injury, neurodegenerative diseases, and early-life stress [46-49] . Alterations in the form and
frequency of physical microglial-axonal contacts, however, have been described in the most detail in
multiple sclerosis (MS) and traumatic brain injury (TBI), therefore this review focuses on these two disease
states [45,50-52] . Many of the changes in microglial-neuronal contacts appear to be dependent on the disease
state, in which there are alterations in microglial associations with specific axonal segments. Below, we
review the interactions of microglial processes with axonal segments, focusing on their associations with
various axonal domains and the unique alterations of these physical interactions in MS and TBI.