Neuronal activity triggers uptake of hematopoietic extracellular vesicles in vivo

Abstract

Communication with the hematopoietic system is a vital component of regulating brain function in health and disease. Traditionally, the major routes considered for this neuroimmune communication are either by individual molecules such as cytokines carried by blood, by neural transmission, or in more severe pathologies, by entry of peripheral immune cells into the brain. In addition, functional mRNA from peripheral blood can be directly transferred to neurons via extracellular vesicles (EVs) but the parameters that determine their uptake are unknown. We show that transfer of EVs from blood is triggered by neuronal activity in vivo. Importantly, this transfer occurs not only in pathological stimulation but also by neuronal activation caused by the physiological stimulus of novel object recognition. This discovery suggests a continuous role of EVs under pathological conditions as well as during routine cognitive tasks in the healthy brain.

Extracellular Vesicles in neural cell interaction and CNS homeostasis

“…Furthermore, transgenic Cre-driver as well as Cre-reporter mouse lines are already available and can be applied for EV research. Using a haematopoietic Cre-driver crossed to stopflox YFP reporter line, it was shown that Cre-containing EVs originating from peripheral immune cells enter the brain and recombine neurons in particular under inflammatory conditions and following increased neuronal activity (100,104). Careful controls such as transplantation of the hematopoietic Cre-driver bone marrow into reporter mice or injection of isolated Cre-carrying EVs were performed to provide the proof that recombination is indeed due to the transfer of EVs and not resulting from reporter leakiness.…”

“…EVs released by cells of the haematopoietic lineage target the brain parenchyma and were shown to transfer cargo including functional Cre reporter mRNA to neurons, which was accompanied by an altered mRNA profile in the recipient cells. This signaling occurred rarely under physiological conditions but was highly elevated in response to different inflammatory stimuli or neuronal activity (100,104). Likewise, inflammatory conditioning triggered human red blood cell (RBC)-EVs, which carry α-synuclein, to Accepted Article enter the mouse brain and target microglia where they induced a pro-inflammatory phenotype.…”