Page 76 - Read Online

Page 254 Benusa et al. Neuroimmunol Neuroinflammation 2020;7:248-63 I http://dx.doi.org/10.20517/2347-8659.2020.03

cystain 3 and hexosaminidase subunit beta. DAM can downregulate homeostatic genes including P2ry12,
Cx3Cr1, and transmembrane protein 119 (Tmem119), and upregulate genes in either a triggering receptor
expressed on myeloid cells 2 (Trem2) dependent (Axl, C-type lectin domain containing 7A, secreted
phosphoprotein 1) or independent (Apolipoprotein E, TYRO protein tyrosine kinase-binding protein)
[91]
manner . Interestingly, another related class of microglia, which present with a similar expression profile
[94]
as DAM , was recently described and named microglial degenerative phenotype (MGnD). It remains to
be determined if MGnD and DAM represent the same subclass of cells.

Although unique to non-homeostatic conditions, the function of DAM is not known. It has been
hypothesized that these cells respond to a CNS stress signaling system that is akin to the peripheral
[96]
immune system’s pathogen- and damage-associated stress signals (PAMPs and DAMPs) . In this scenario,
danger signals are recognized by microglia and trigger the transition of surveying microglia into DAM.
This hypothesis is consistent with DAM accumulation in Alzheimer’s Disease plaques and regions of
demyelination [91,94,97,98] . If correct, DAM would be a key component of an intrinsic mechanism designed
to combat disease processes and could provide a promising target for therapeutic manipulation against
neurodegenerative disease by further enhancing the DAM response.

Heterogenic expression in inflammatory microglia
Following injury or disease, reactive microglia are rapidly recruited to sites of damage where they
phagocytose debris and dying cells, consistent with the described functions of DAM. Likewise, AXIS
microglia may also be recruited to sites of damage following injury or disease [80,81] . However, unlike DAM,
the expression profile of AXIS microglia has not been characterized. Instead, AXIS microglia have been
characterized based on their physical interactions with the axonal domain of the AIS. Both surveying
and reactive microglia make contact with AISs and this is increased or decreased based on the disease
context [78,79] . Whether these cells provide trophic support at the AIS or drive pathogenesis remains unclear
though. Reactive microglia also exhibit extensive changes in expression of their inflammatory profile .
[99]
While some of these secreted factors may provide neurotrophic functions, pro-inflammatory factors can
also exhibit deleterious effects [100,101] . For example, pro-inflammatory microglia (“M1”) upregulate enzymes
that produce reactive oxygen species (ROS) [100] . Activation of microglial nicotinamide adenine dinucleotide
phosphate (NADPH) oxidase (NOX2) results in the extracellular production of ROS [102] . ROS then alter the
function of calcium-permeable ion channels [103-105] and consequently, alters intracellular calcium levels [105,106] ,
which have been implicated in AIS disruption [81,107-110] .

In addition to regulating neuronal function through secreted factors, microglia also regulate neurons
through physical contact [82,111-115] . In the developing and adult brain, microglia contact pre- and postsynaptic
neuronal elements in an activity-dependent manner, and synapses that are contacted more frequently
are subsequently removed [17,115,116] . In pathological conditions, microglia participate in synaptic stripping
[16]
altering the neuronal excitatory/inhibitory balance . Microglia also preferentially contact cell bodies and
axons of highly active neurons to decrease neuronal activity and prevent excitotoxic cell death [113,114] . These
studies underscore the importance of microglial contact in the regulation of neural signaling.

Recently, we analyzed CNS pathology in three models of neuroinflammation. In all three models, microglia
presented with reactive phenotypes and these cells maintained, or even increased, contact with the AIS.
However, in two of the models, the AISs were disrupted and in one, the AISs were preserved. Since AIS
integrity temporally correlated with the presence of reactive microglia and contact was at least maintained
in all three models, we proposed that differential AIS integrity was consequential to the heterogeneity
among the reactive microglia from all three models.

[79]
[80]
For our studies, we exploited the immune-mediated inflammatory models of EAE , LPS and the
demyelinating model of cuprizone . The EAE model is induced through subcutaneous injection of
[79]