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Sahu et al. Neuroimmunol Neuroinflammation 2018;5:2 I http://dx.doi.org/10.20517/2347-8659.2017.43 Page 3 of 14

circulation, have access to the CNS when the blood brain barrier (BBB) is compromised. In addition, with
the latest discovery of lymphatic vessels between the meninges and skull bones, inflammatory mediators
may have easier access to brain tissues. Even though these cells act as a defense system, they could contribute
to cellular damage when excessively deployed in the interstitial space. Inflammation in the brain becomes
chronic, and often pathological, when usually acute inflammation ceases in a short period and does not
contribute to repair.

The microglia activation mechanism is an important determinant in the protection of the neural parenchyma
in response to various infections, neuroinflammation, stroke, tumors, trauma, and neurodegenerative
diseases . Through a variety of mechanisms, activated microglia are the first cells in the CNS to respond
[15]
to neuronal damage; they are usually able to exert two opposing functions both promoting neuronal
regeneration, and killing neurons [15,16] . Exerting either function is largely determined by the particular
[16]
conditions that evoke microglial activation . However, the specific nature of any such constructive or
destructive mechanisms remains nebulous.

Activated microglial cells release a number of cytotoxic molecules in vitro, (i.e. proteases, reactive oxygen
intermediates, NO, cytokines, arachidonic-acid derivatives, excitatory amino acids, and quinolinic acid) [17-19] .
HIV-infected mononuclear cells are known to produce low molecular weight neurotoxins, possibly causing
[20]
neuronal damage via N-methyl-D-aspartate receptors . The cytokine tumor necrosis factor-α (TNF-α)
in the CNS produced by microglial cells could cause bystander damage during the demyelination process.
Moreover, the free oxygen radicals released by microglia have a direct toxic effect, as evident in co-cultures of
neurons and microglia . Mostly information on the cytotoxic properties of activated microglia are obtained
[21]
from in vitro cultures, and has not yet been replicated in vivo. Furthermore, the cytotoxic properties of
microglial cells are subject to considerable species variation; NO production is established for rat microglia,
[22]
but in humans astrocytes might contribute to NO synthesis in addition to microglia .

AUTOPHAGY AND ITS REGULATING FACTORS UNDER PHYSIOLOGIC CONDITIONS
Autophagy is a cellular process that facilitates delivery of cytoplasmic constituents of eukaryotic cells for
lysosomal degradation for nutrients recycling, and survival during starvation . Physiologically, autophagy
[23]
removes damaged or obsolete intracellular organelles. Meanwhile, it protects the body against microbial
[24]
invasion by eliminating intracellular pathogens .

Autophagy is induced by both metabolic and immune signals, comprised of pathogen recognition and
proinflammatory cytokine mediated stimulation .
[25]

There are three different types of autophagy known to occur in mammalian cells. (1) Macroautophagy-
which relies on cytosolic double-membrane vesicle (autophagosomes) formation de novo, to sequester and
transport cargo to the lysosome. (2) Chaperone-mediated autophagy-where individual unfolded proteins
are transported directly across the lysosomal membrane. (3) Microautophagy- involving the direct uptake
of cargo through invagination of the lysosomal membrane. All these types of autophagy ultimately lead to
degradation of cargo and release of the breakdown products back into the cytosol for reuse by the cell .
[26]

[27]
The degradative autophagy pathway is activated upon starvation, mediated through a protein kinase (Tor) . This
kinase might also inhibit the autophagy pathway, either by acting in a signal transduction cascade through
[28]
various downstream effectors, or by causing the ATG13 hyperphosphorylation . Phosphorylated ATG13
has a lower affinity for the ATG1 kinase, and thereby a reduced interaction might inhibit the autophagy
process . The Gcn2, along with its targets, eIF2α, and the Gcn4 transcriptional transactivator proteins in
[29]
the downstream, might also play a role in induction of autophagy .
[30]