MP-Associated Bioactive Agents in Neuroinflammation

Micro-RNA (miRNA)

A giant step in neuroscience, cancer research, and other fields was the discovery that MP can transport active RNA oligomers from cell to cell, both naturally and by therapeutic design. Among these are small interfering RNA (siRNA) which can silence or modulate the expression of specific genes.

For example, it was demonstrated that expression of MiR-155 in microglial cells regulated replication of the Japanese encephalitis virus and modulated aspects of innate immunity such as complement [46]. Nucleotides bound to MP/exosomes are protected against degradation by plasma enzymes. Cell-to-cell transfer of miRNA via MP has been shown to exert major modulation of neuroinflammatory responses, as in brain infection [47].

The several phenotypes of MP/exosome that arise from a single lineage, such as monocytes, exhibit varying RNA content and transcripts: MP-bearing transcripts of pro-inflammatory cytokines (such as TNF, IL-6, IL-8) when incubated with human brain endothelial cells (EC) led to the uptake of the MP and, unexpectedly, promoted tightness of EC monolayer junctions in tissue culture, measured by impedance and directly by permeability [48]. Frohlich et al. observed a variety of effects of MP transferred from stimulated oligodendrocytes to neurons [49].

Pusic and Kraig, after commenting on myelination in MS, report isolating exo- somes from old vs. young animals with enriched environment and found that the latter but not the former promoted myelination when administered intranasally; this effect was attributed to MiR-219 [50]. In a similar vein, oxidized LDL particles were observed to “epigenetically reprogram” monocytes [51].

As earlier noted, MP can also transport DNA fragments, e.g., [11]. Patients with MS on natalizumab therapy are prone to polyomavirus; the MP/exosomes from plasma or urine, and from mononuclear cells, all contained transcripts of the virus in infected subjects [52]. It is beyond the scope of this review to consider the role of MP in viral infections but a large literature on this subject exists. Very recently, the first known instance of DNA interference in an animal was reported [52b], leading us to expect more on this in the future.

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