The nervous and immune systems are the two most complex systems in the body. That
complexity is amplified by the fact that each influences the other, as they constantly
exchange messages in response to environmental and internal cues. The best known messages
from immune cells are the cytokines, which trigger changes within neurons through
well-established receptor-initiated cascades. But in a new study in this issue of
PLOS Biology, Kirsten Ridder, Stefan Momma, and colleagues show that hematopoietic
cells, which include the cells of the immune system, release messenger RNAs (mRNAs)
and microRNAs (miRNAs) that are absorbed by neurons. This mechanism of signaling is
elevated in response to inflammation, and the transferred RNAs have the potential
to influence neuronal responses.
Inflammation has recently been shown to drive an even more unexpected neuro–immune
interaction—fusion of hematopoietic cells with Purkinje neurons of the cerebellum,
in which the resulting cell contains both nuclei. The authors sought to determine
whether less drastic transfers of genetic messages might be taking place as well.
To do so, they relied on the Cre recombination system. In this system, a gene of interest
is engineered to be flanked by target sequences (“lox” sequences) for the enzyme Cre
recombinase. Enzymatic action rearranges the site and triggers expression of the gene
within. Here, the authors used mice with a lox-flanked reporter gene in all tissues.
The Cre recombinase gene, though, was introduced only to hematopoietic cells. Thus,
any non-hematopoietic cells expressing the reporter gene must have picked up either
the Cre recombinase gene, its mRNA, or the protein itself, from hematopoietic cells.
The authors found that a small number of Purkinje neurons expressed the reporter,
despite the absence of any double nuclei (ruling out cell fusion as described above
and therefore gene transfer). So how were the neurons getting the message? Extracellular
vesicles (EVs) have lately emerged as a significant vehicle for trafficking multiple
kinds of molecules between cells, including proteins and mRNAs, so the authors isolated
EVs from peripheral blood. When they analyzed the contents, they found the EVs contained
Cre recombinase mRNA, but not the protein.
In healthy mice, the number of Cre-recombined neurons was very low, far less than
1%. But when the authors triggered a peripheral inflammatory response that number
jumped by several orders of magnitude, affecting an average of 6% of Purkinje neurons.
Under such conditions of inflammation, several other types of brain neurons were also
targeted, including those in the hippocampus, cortex, and substantia nigra.
These results show that mRNA can be transferred from immune cells of the peripheral
blood to neurons of the central nervous system via EVs. It remains to be seen whether
other immune-derived mRNAs take advantage of the same means of transport to enter
neurons.
But known exosome passengers also include miRNAs, short non-coding RNAs that influence
gene expression in many types of organisms. By excising single neurons, the authors
showed that Cre-recombined neurons contained three miRNAs not found in non-recombined
neurons; the same three were also present in exosomes isolated from blood in mice
experiencing inflammation. These results suggest that the three miRNAs could derive
from the same immune cells as the Cre recombinase. If that is so, this study indicates
there is not only another medium of information exchange between the immune and nervous
system but also a whole new type of message, and it suggests that the regulation of
the nervous system by the immune system may be more extensive and intimate than previously
appreciated.
10.1371/journal.pbio.1001875.g001
Purkinje neurons express a reporter gene upon uptake of RNA from hematopoietic extracellular
vesicles. The number of these vesicle-targeted cells increases in response to inflammation.
Image Credit: Stefan Momma, Jadranka Macas
Ridder K, Keller S, Dams M, Rupp A-K, Schlaudraff J, et al. (2014) Extracellular Vesicle-Mediated
Transfer of Genetic Information Between the Hematopoietic System and the Brain in
Response to Inflammation.
doi:10.1371/journal.pbio.1001874.