The Messenger Apps of the cell: Extracellular Vesicles as Regulatory Messengers of Microglial Function in the CNS.

The intense effort of investigators, in particular during the past decade, has highlighted the importance of extracellular vesicles (EVs) such as exosomes in regulating both innate and adaptive immunity in the course of a variety of infections, with clear implications for development of novel vaccines, therapeutics, and diagnostics. Current and future efforts now need to focus strongly on teasing apart the intricate and complex molecular mechanisms that operate during EV regulation of immunity. In this review, we discuss recent advances that bear on our current understanding of how EVs, including exosomes, can contribute to the innate immune functions of microglia within the central nervous system (CNS), and we also highlight future important mechanistic questions that need to be addressed. In particular, recent findings that highlight the crosstalk between autophagy and exosome pathways and their implications for innate immune functions of microglia will be presented. Microglial activation has been shown to play a key role in neuroAIDS, a neuro-infectious disease for which the importance of exosome functions, including exosome-autophagy interplay, has been reported. The importance of exosomes and exosome-autophagy crosstalk involving microglia has also been shown for the Parkinson's disease (PD), a neurodegenerative disease that is thought to be linked with immune dysfunction and involve infectious agents as trigger. Considering the accumulation of recent findings and the vibrancy of the EV field, we anticipate that future studies will continue to have a deep impact on our understanding of the CNS pathologies that are influenced by the functions of microglia and of the infectious disease mechanisms in general. Graphical Abstract.