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The Nkx and Sox families also play roles in to attack myelin, demyelinated axons, and dying
oligodendrogenesis, even though they are not critical. motoneurons through the activation of the perforin
[84]
Ablation of Nkx6.1/Nkx6.2 blocks the production pathway, the delivery of granzymes into the cells,
of both oligodendrocytes and motoneurons in the or by Fas‑Fas ligand interactions. [86] Additionally, B
pMN. [70,71] Additionally, Sox9 knockout mice show lymphocytes produce autoantibodies against myelin
deficits in glial specification, presenting a reduced antigens, degrading myelin sheath. Because infiltrating
number of oligodendrocytes and astrocytes. [72] effector T cells, microglia and macrophages release
Furthermore, if there is a Sox8/Sox9 double inactivation, cytokines and chemokines, inflammation will be
no oligodendrocytes are produced, which suggest that exacerbated and consequently more T cells, B cells,
Sox8 and Sox9 serve redundant functions in relation and innate immune cells will be recruited to the lesion
to oligodendrogenesis. [72] site, contributing to chronic neuroinflammation, and
neurodegeneration [Figure 3]. [87]
In the last few years, epigenetic modulation of
oligodendrogenesis has been gaining some importance, Neuroinflammatory responses can be deleterious
namely regarding the modulation by microRNA and for cell survival, resulting in irreversible extensive
histone modifications. One of the most described damage to the brain, especially if they are prolonged
microRNA in oligodendrogenesis is miRNA‑7a. This in time. [88] However, they have also been described
miRNA is highly enriched in OPCs and overexpressing as having beneficial effects and as being critical for
it in neuronal progenitors during brain development the activation of the brain repair process, such as
promotes OPC commitment, both in vivo and in vitro. [73] for the remyelination program. As a result of white
In contrast, blocking miRNA‑7a function inhibits OPC matter damage, there is an accumulation of apoptotic
generation and favors neuronal progenitors. [73] cells and myelin debris in the lesion site, which
have been demonstrated to be inhibitory to axonal
Histone modifications can also be important for regeneration, as well as affecting OPC differentiation
oligodendrogenesis. For instance, it has been into mature myelinating oligodendrocytes. However,
shown that oligodendrocyte production from NSCs, through phagocytosis of cellular debris and apoptotic
instead of other cellular fates, depends on histone cells, microglia and brain infiltrating macrophages
deacetylases (Hdac) activity. [85] Similarly, a study using function toward repairing the damaged tissue, by
Enhancer of zeste homolog 2 (Ezh2), a polycomb group promoting a pro‑regenerative environment, promoting
protein involved in gene silencing through histone OPC recruitment and differentiation, thus favoring
methylation, provided evidence that a higher rate of remyelinaton and axonal regeneration. [29,89‑91] For
histone methylation (via Ezh2 overexpression) leads to instance, ROS hydrogen peroxide (H O ), released by
2
2
an increase in oligodendrocyte production [Table 1]. [74] macrophages and microglia, destroys damaged cells,
affecting not only healthy surrounding cells, but also
IMMUNE MEDIATORS OF OLIGODENDROGENESIS promoting proliferation and differentiation of NSCs
into oligodendrocytes. [92] Astrocytes have also been
When white matter is damaged as a result of an described to have an important, yet controversial, role
infection, a trauma or a neurodegenerative disease in demyelinating diseases. Astrocytes have been shown
such as MS or vascular dementia, microglia, the to have an important role in both demyelination and
brain’s innate immune cells, are activated. Microglia remyelination. [93‑95] On the one hand, because astrocytes
removes infectious agents and apoptotic cells, through are antigen‑presenting cells and release cytokines and
phagocytosis and by producing reactive oxygen chemokines, they contribute to myelin damage through
species (ROS), TNF‑α, nitric oxide (NO), IL‑1β, and an immune‑mediated demyelination by recruiting
prostaglandin E2. [86] When microglia are chronically inflammatory cells, such as T lymphocytes, microglia,
activated, sustained release of inflammatory and macrophages to the lesion site. [95] On the other
factors, cytokines, and chemokines compromises hand, astrocytes are described as being responsible for
the blood‑brain barrier (BBB), resulting in vascular a successful remyelination through the regulation of the
permeability to blood and circulating immune cells, clearance of myelin debris [94] and oligodendrogenesis
such as T and B lymphocytes and macrophages, as in the lesion site [Table 2]. [93] Astrocytes promote
well as recruitment of these peripheral immune cells OPC migration, proliferation, and differentiation after
to the lesion site. [87] By recognizing their specific demyelination by secreting several factors, which
autoantigen presented by MHC class II molecules on have an impact on myelin repair. [93] In fact, several
+
the surface of antigen presenting cells, CD4 T cells cytokines and chemokines produced by microglia,
are activated and attack the myelin sheath. [87] Antigens macrophages, and astrocytes in response to brain
on MHC class I molecules also activate CD8 T cells injury have been described as having an essential
+

268 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 269