EXOSOME RELEASE PROMOTES INFLAMMATORY RESOLUTION IN ACTIVATED AND AGED MICROGLIA

Proper regulation of inflammatory responses is critical for effective function of microglia, in both physiological and disease states. While the mechanisms that drive microglia activation are well characterized, the pathways leading to inflammatory resolution and immune homeostasis have yet to be fully elucidated. Using RNA interference, pharmacological inhibition and genetic knockout mouse model approaches, we show that exosome release promotes immune homeostasis in activated and aged microglia. We demonstrate that induction of anti-inflammatory pathways enhances release of exosomes containing immune proteins and microRNAs. Functionally, inhibition of exosome release alters trafficking of exosome cargo, such as miR-155, in activated microglia resulting in increased cellular retention of these cargo molecules. Concordantly, we identify increased miR-155 activity leading to sustained activation of pro-inflammatory pathways as a potential mechanism underlying impaired inflammatory resolution due to inhibition of microglia exosome release. Similarly, inhibition of augmented exosome release in aged microglia exacerbates inflammatory activation, demonstrating conservation of the immune modulatory effects of exosome release in microglia. Taken together, our study identifies exosomes as novel components of an anti-inflammatory mechanism utilized by activated and aged microglia to restore immune homeostasis.