Page 80 - Read Online

Page 258 Benusa et al. Neuroimmunol Neuroinflammation 2020;7:248-63 I http://dx.doi.org/10.20517/2347-8659.2020.03

based on cluster comparisons, which is in contrast to previous reports [48,50,54,128] . Although sex differences
were not observed, significant differences were observed within the aged brain (postnatal day 540) as
certain clusters, which were comprised of very few cells in the adult brain (postnatal day 100), revealed a
significant increase in the number of cells in the aged brain. Perhaps most interesting is the finding that
specific subpopulations of microglia were similarly represented in demyelinating lesions in the mouse and
human brains, suggesting that microglial cluster expression profiles may allow identifying disease-specific-
“fingerprints”, and eventually aid in human disease treatment.

CONCLUSION
Although described 100 years ago, we are only just beginning to put together the various pieces of the
microglial puzzle. We now recognize their involvement in establishing and maintaining a homeostatic CNS
environment through trophic support and pruning of both neuronal and glial populations, modulating
CNS wiring and circuitry, and facilitating axonal organization and outgrowth, myelin formation, and
immunosurveillance in the healthy brain. Moreover, we are also beginning to appreciate their critical roles
in disease, potentially both as CNS protectors by recognizing and removing infected, dying and dead cells,
and also as CNS villains secondary to hyperactivation or dysregulation. We are also beginning to recognize
that microglia may present as functionally distinct subclasses, which provides an explanation as to how a
single lineage cell type can manifest into a plethora of diverse roles. However, it remains to be determined
if distinct subclasses of microglia truly exist, or if microglia exist on a spectrum where they have the
capacity to take on a multitude of identities depending on their environment. To address this issue,
consistent approaches in cell isolation and analysis should be established and implemented. Additionally, as
[86]
presented by other authors , the generation of a naming scheme that incorporates all aspects (age, brain
region, morphology, gene expression, function, etc.) of microglia is essential for effectively moving the field
forward. Although much has been learned over the past 20 years, our understanding of microglia remains
limited. The immediate future though should be viewed with excitement as we continue to unravel the
mysteries of these enigmatic cells.

DECLARATIONS
Authors’ contributions
Made substantial contributions to experimental conception and design and manuscript preparation:
Dupree JL
Made substantial contributions to experimental conception and design, in technical support, mRNA data
analysis and interpretation and manuscript preparation: Benusa SD
Made substantial contributions to microglia-AIS contact analysis and interpretation: George NM

Availability of data and materials
NanoString raw data files are provided in Supplementary Material.

Financial support and sponsorship
This work was supported by grants from the National Institute of Health [“Microglial neurofascin: a
novel mediator of microglial/axon initial segment interactions?” R21NS1016515; (JLD)] and the Veterans
Affairs [“Attenuating microglial-dependent axonal pathology in EAE” (No. BX002565 (JLD)]. Microscopy
was performed at the VCU Massey Cancer Center Microscopy Core Facility and supported, in part, with
funding from NIH-NCI Cancer Center Support Grant P30 CA016059.

Conflicts of interest
All authors declared that there are no conflicts of interest.