Innate immune system crosstalk: Eosinophils mediate immune modulation of dendritic cells through exosomes as shuttle vectors of miRNA

Schorer, Myriam Fabiola; Simon, Dagmar (2016). Innate immune system crosstalk: Eosinophils mediate immune modulation of dendritic cells through exosomes as shuttle vectors of miRNA (Submitted). (Dissertation, Graduate School for Cellular and Biomedical Sciences, University of Bern, Faculty of Medicine)

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Eosinophil granulocyte infiltration is a predominant feature of allergic immune
responses. However, despite being significant players in these disorders, the exact function of eosinophils in the pathogenesis and interaction with other immune cells remains to be explored. Our results show that eosinophils and dendritic cells (DCs) chemoattract each other and rapidly form stable conjugates that persist for long time periods; importantly, eosinophils-DCs conjugates in skin biopsies of patients with eosinophilic diseases were observed. Functional assays revealed the importance of this crosstalk, as eosinophils were capable of activating DCs, subsequently triggering an immune response. Interestingly, DCs were more efficiently activated upon
physical interaction with eosinophils, suggesting that the physical crosstalk facilitates the functional delivery of activatory mediators into the DCs. Thus, the molecular association of this novel innate immune system crosstalk was further investigated, and the formation of an immunological synapse (IS) was observed, as assessed by the polarization of actin and adhesion molecules towards the site of contact between
eosinophils and DCs. Additionally, in line with recent reports highlighting the transfer of RNA via exosomes as a novel mode of intercellular communication, polarization of CD9, an exosome marker, to the IS between eosinophils and DCs was observed. To prove this novel mechanism in functional assays, exosomes were isolated from eosinophils and cultured with DC; indeed, DCs fully maturated, implicating intercellular exosomes transfer through the IS as a mechanism for eosinophil activation of DCs. Therefore, these results unveil a novel role of eosinophils in the activation of DCs to orchestrate allergic immune responses, which besides the new mechanistic insights, disclose potential novel treatment approaches for allergic or hypereosinophil chronic inflammatory diseases.

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