Abstract
In contrast to peripheral macrophages, microglia in the central nervous system (CNS) exhibit a specific deactivated phenotype; however, it is not clear how this phenotype is maintained. Two alternative hypotheses were postulated recently: (a) microglia differ from peripheral macrophages being derived from the yolk sac (YS), whereas peripheral macrophages originate from bone marrow (BM); (b) microglia acquire a specific phenotype under the influence of the CNS microenvironment. We have previously shown that microglia express miR‐124, which was also induced in BM‐derived macrophages co‐cultured with a neurons. We here investigated the possibility of horizontal transfer of the neuron‐specific microRNAs miR‐124 and miR‐9 from primary neurons to microglia/macrophages. We found that after incubation with neuronal conditioned media (NCM), macrophages downregulated activation markers MHC class II and CD45. Neither cultured adult microglia nor YS‐ and BM‐derived macrophages demonstrated intrinsic levels of miR‐124 expression. However, after incubation with NCM, miR‐124 was induced in both YS‐ and BM‐derived macrophages. Biochemical analysis demonstrated that the NCM contained miR‐124 and miR‐9 in complex with small proteins, large high‐density lipoproteins (HDLs), and exosomes. MiR‐124 and miR‐9 were promptly released from neurons, and this process was inhibited by tetrodotoxin, indicating an important role of neuronal electric activity in secretion of these microRNAs. Incubation of macrophages with exogenous miR‐124 resulted in efficient translocation of miR‐124 into the cytoplasm. This study demonstrates an important role of neuronal miRNAs in communication of neurons with microglia, which favors the hypothesis that microglia acquire a specific phenotype under the influence of the CNS microenvironment.
Highlights
It is currently accepted that the central nervous system (CNS) pos‐ sesses a specialized immunosuppressive microenvironment for im‐ mune cells such as macrophages, which often demonstrate a low level of activation in the normal CNS and even during various pa‐ thologies such as neuroinflammation
Because we found that neuronal mi‐ croRNA‐124 is expressed in CNS‐resident microglia but not in pe‐ ripheral macrophages (Ponomarev, Veremeyko, Barteneva et al, 2011), we hypothesize that there is a horizontal transfer of neuronal microRNAs from neurons to microglia
It is especially impor‐ tant in the case of microglia since our study strongly suggest that these cells acquire their deactivated MHC class IIlowCD45low in the CNS microenvironment upon communication with electrically ac‐ tive neurons
Summary
It is currently accepted that the central nervous system (CNS) pos‐ sesses a specialized immunosuppressive microenvironment for im‐ mune cells such as macrophages, which often demonstrate a low level of activation in the normal CNS and even during various pa‐ thologies such as neuroinflammation. We found that only microglia (but not other types of tissue‐resi‐ dent or blood‐derived macrophages) expressed neuronal microRNA miR‐124, which mediated their deactivated MHC class IIlowCD45low phenotype (Ponomarev, Veremeyko, Barteneva, Krichevsky, & Weiner, 2011). It remains unknown how the expression of miR‐124 is induced in microglia. Postsynaptic terminals are significantly enriched with neuronal lipid rafts found in the area of post‐synaptic density (Ponomarev, 2018; Sotnikov et al, 2013) and may serve as an additional external site for miRNA binding for subsequent release into the extracellular space via shedding and/or enzymatic cleavage of glycosphingolipids (e.g., sphingomyelinase, β‐ galactosidase) (Janas et al, 2015, 2006; Khvorova et al, 1999).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
