Abstract
Author SummaryPeripheral infections leading to an inflammatory response can initiate signaling from the hematopoietic system to various organs including the brain. The traditional view of this communication between blood and brain is that individual factors are released by immune cells that in turn bind to neuronal or nonneuronal target cells in the brain where they exert their effects. By using a genetic tracing system, we now show that extracellular vesicles, small membrane structures that can contain a multitude of different molecules, can transfer functional RNA directly from blood cells to neurons. Although this type of signaling is highly restricted in the healthy animal, inflammatory injuries increase both the frequency of transfer and the range of the neuronal target populations in the brain. By showing altered miRNA profiles in neurons receiving extracellular vesicle cargo, we predict a complex regulation of gene expression in neural cells in response to peripheral inflammation.
Highlights
The influence of the immune system on the brain in the context of inflammation is highly relevant for a number of diseases, yet mechanisms for this interaction are not fully understood
By using a genetic tracing system, we show that extracellular vesicles, small membrane structures that can contain a multitude of different molecules, can transfer functional RNA directly from blood cells to neurons
The number of fusion events is very low in the healthy animal, peripheral inflammation induces cell fusion events to increase by a factor of 10–100, giving the first indication that heterotypic fusion is regulated by a pathologic stimulus and may be of biological significance [5]
Summary
The influence of the immune system on the brain in the context of inflammation is highly relevant for a number of diseases, yet mechanisms for this interaction are not fully understood. The stereotypical response is the secretion of proinflammatory cytokines by immune cells. These peripheral cytokines in turn can have a direct effect on neural cells or activate brain inflammatory cytokine signaling, usually via microglia, the principle innate immune cells of the brain [1]. Heterotypic cell fusion of hematopoietic cells with Purkinje neurons in the brain has been suggested as a conceptually different mechanism of response to inflammation. Seen as evidence for an unexpected differentiation potential of hematopoietic stem cells, it was eventually demonstrated that the experimentally observed plasticity was largely attributable to cell fusion, rather than transdifferentiation [2,3,4]
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