Extracellular vesicle-mediated transfer of genetic information between the hematopoietic system and the brain in response to inflammation

PLoS Biol. 2014 Jun 3;12(6):e1001874. doi: 10.1371/journal.pbio.1001874. eCollection 2014 Jun.

Abstract

Mechanisms behind how the immune system signals to the brain in response to systemic inflammation are not fully understood. Transgenic mice expressing Cre recombinase specifically in the hematopoietic lineage in a Cre reporter background display recombination and marker gene expression in Purkinje neurons. Here we show that reportergene expression in neurons is caused by intercellular transfer of functional Cre recombinase messenger RNA from immune cells into neurons in the absence of cell fusion. In vitro purified secreted extracellular vesicles (EVs) from blood cells contain Cre mRNA, which induces recombination in neurons when injected into the brain. Although Cre-mediated recombination events in the brain occur very rarely in healthy animals, their number increases considerably in different injury models, particularly under inflammatory conditions, and extend beyond Purkinje neurons to other neuronal populations in cortex, hippocampus, and substantia nigra. Recombined Purkinje neurons differ in their miRNA profile from their nonrecombined counterparts, indicating physiological significance. These observations reveal the existence of a previously unrecognized mechanism to communicate RNA-based signals between the hematopoietic system and various organs, including the brain, in response to inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Exosomes / metabolism*
  • Hematopoietic System / metabolism*
  • Inflammation / metabolism*
  • Integrases
  • Mice, Transgenic
  • Purkinje Cells / metabolism*
  • RNA, Messenger / metabolism*
  • Recombination, Genetic

Substances

  • RNA, Messenger
  • Cre recombinase
  • Integrases

Grant support

This study was supported by the Edinger Foundation and the Deutsche Forschungsgemeinschaft (DFG, grant DFG MO 2211/1-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.