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Page 10 of 14 Sahu et al. Neuroimmunol Neuroinflammation 2018;5:2 I http://dx.doi.org/10.20517/2347-8659.2017.43

REGULATION OF AUTOPHAGY IN PERIPHERAL NEURONS
For decades, autophagy has been closely associated with both nutrient acquisition and pathogen destruction.
In the apparent coevolution with pathogens, adaptive immune protection mechanisms of higher eukaryotic
organisms such as human beings have also learned to exploit autophagy. Autophagy has evolved from a
nutrient providing pathway to one which aids in higher functions in the innate, adaptive and cell-intrinsic
immunological pathways.

Hence, it is not a surprise that autophagic pathways do indeed cross talk with innate immunity mechanisms,
contributing to the combat of pathogenic infiltration. Though research into how pathogens obtain nutrients
remains in its infancy, it has always been speculated that pathogens require autophagy as one of the many
sources of intracellular nutrients, to survive and propagate in their host cells. All aspects considered, the
critical questions that remain unanswered are, which nutrients do pathogens acquire from autophagy, and
what is the degree to which they rely on these nutrients.

Neuronal autophagy is regulated uniquely, andis also adapted to a great extent along with local axonal
physiology. Moreover, the detailed mechanism for neuronal autophagy might be significantly different to
classically induced autophagy. In recent times, several studies have shown the importance of autophagy in
various neurodegenerative conditions; studies have also identified autophagic process to be a potential target
in drug discovery. Therefore, further understanding of the process of autophagic death of neuronal cells
would eventually aid in novel drug target identification and rational designing of drug screening protocols
in order to combat various neurodegenerative conditions .
[73]

It is a good idea to identify some therapeutic agents that can control autophagy during infection, particularly
when massive autophagic neural cell death causes the major pathology that might be induced possibly by
some pathogen factors. Therapeutic manipulation of the interactions between autophagy and inhibitory
cytokines might represent a novel method of regulating the immune response, and thereby a more facilitated
clinical translation .
[12]
Only very limited information is available on possible therapeutics to inhibit autophagy in terms of
providing protection, particularly in the case of excessive autophagic death in neurodegerative disorders.
Inhibiting transglutaminase 2 (TG2), which is a multifunctional protein having implications in diverse
pathophysiological processes, might offer a novel therapeutic approach for managing excessive autophagy .
[74]
Inhibition of the enhancer of zeste homolog 2 (EZH2) gene expression has also been shown to inhibit
autophagy significantly, as reported in a study on human ovarian cancer where EZH2 expression could
reverse the cisplatin resistance by inhibiting autophagy . Downregulation of the methionine synthase
[75]
reductase (MTRR) gene might also be an approach to inhibit the PI3K/Akt autophagy pathway; in a recent
study, MTRR silencing could significantly increase cisplatin-induced apoptosis and reduce the autophagy
[76]
induced by cisplatin in SKOV3/DDP cells . The glucose regulated protein 78 (GRP78) is also known to
affect autophagy and apoptosis; particularly in ovarian cancer cells. GRP78 is reported to have a regulatory
role in expressions of Beclin1, Bcl-2 and CHOP, thereby affecting the sensitivity to cisplatin in ovarian
carcinoma, which may be a new method for ovarian carcinoma treatment through improvement of the
sensitivity to cisplatin. However, there is no study done to validate such hypotheses regarding the possible
role of inhibiting excessive neurodegeneration due to autophagy in minimizing the bulk self-digestion of
the neuronal cells.

CONCLUSION AND RECOMMENDATION
The presence of antigenic stimuli of pathogens can induce autophagic genes through a stratified array of
principal immunologic processes, and therefore result in augmented autophagy and inflammation at the