Activated monocyte-derived exosomes transfer MIR-223 to neural cells: impact of peripheral inflammation on cognitive impairment

Archana Gupta

doi:10.17918/00000830

Chronic inflammatory diseases characterized by immune activation are often associated with neurocognitive deficits; however, the mechanism(s) by which inflammation in the periphery impact the CNS remain elusive. Using HIV/HCV-infection as a model for chronic inflammatory disorders, we investigated a novel mechanism of neurocognitive impairment mediated by activated monocyte-derived exosomes. Exosomes are a class of extracellular vesicles that facilitate cell-to-cell communication by the transfer of host RNA, including miRNAs and proteins. Several lines of evidence suggest that exosomal miRNAs are functional in recipient cells and are involved in the pathogenesis of several disorders including neuroinflammatory diseases. We recently reported that 60% of subjects with HCV and virally-suppressed HIV infection (coinfection) were cognitively impaired. Importantly, we showed that peripheral monocytes from coinfected subjects with undetectable HIV demonstrate an IFNa gene activation profile that correlates with cognitive deficits. Since HCV is not considered neurotropic, it suggests that indirect viral mechanisms may be responsible for neural cell dysfunction. We hypothesized that IFNactivated monocyte/macrophages mediate neurocognitive impairment in coinfection by the transfer of exosomal miRNAs to neural cells that subsequently dysregulate their function. In support of our hypothesis, we show that monocyte-derived exosomes are internalized by primary human astrocytes. In addition, global miRNA profiling of exosomes shed by monocytes from HIV/HCV-infected subjects revealed that miR-223 was the most abundant miRNA in the vesicles. Further, we developed an in vitro model that recapitulated the activation state of monocytes from coinfected subjects. IFNactivated monocyte-derived exosomes were also highly enriched in miR-223, and when incubated with astrocytoma cells, resulted in significant elevation of intracellular miR223 levels suggesting exosomal miRNA tranfer. Importantly, we demonstrate that exosomal miR-223 from activated monocytes is functional in astrocytoma cells and suppresses the expression of CYP26B1, a putative miR-223 target that is vital for the maintenance of retinoic acid homeostasis in the brain. That exosomal miRNAs shed by activated immune cells can alter brain function has great implications on our current understanding of the pathogenesis of CNS disorders characterized by inflammation in the periphery.

Activated monocyte-derived exosomes transfer MIR-223 to neural cells: impact of peripheral inflammation on cognitive impairment

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Activated monocyte-derived exosomes transfer MIR-223 to neural cells: impact of peripheral inflammation on cognitive impairment

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