Francis Crick Institute scientists have discovered that
fruit flies and humans have much in common when it comes to
inflammatory responses to stress or injury. Their research gives
insights into human diseases and possible new
treatments.
Drosophila fruit flies were used as a model for the
response to actin due the powerful genetics in that organism as
well as their lack of redundant genes. However the findings will
lead the way for future investigations into if and how
extracellular actin drives inflammation in mammals, including
humans.
Things like trauma, burns or strenuous exercise all cause
an inflammatory response. But unlike inflammation caused by
infection, no microbes need to enter the body - which is why this
is called a sterile inflammatory response. While sterile
inflammation generally serves an important purpose, if
uncontrolled, it's thought to contribute to many diseases, from
cancer to neurodegeneration. All animals need to be
able to detect injuries so they can set in motion the inflammatory
responses that pave the way for tissue repair.
Sterile inflammatory responses are initiated by signals from
damaged cells. These signals include molecules from inside cells
that become exposed when the cells' membranes become leaky. The
signals are known as damage-associated molecular patterns
(DAMPs).
Work led by Francis Crick Institute scientists studying
Drosophila fruit flies has revealed that actin, an abundant protein
that makes up part of the cell cytoskeleton, can act as a DAMP and
can induce sterile inflammatory responses. The findings have
implications for human diseases where actin has been found in
places where it shouldn't be - indicating that in some cases the
protein might be prompting harmful inflammatory responses and
worsening disease.
Naren Srinivasan and Oliver Gordon in Caetano Reis e Sousa's
group at the Crick carried out much of the work. They explain:
"Sterile inflammation can be initiated when molecules that are kept
inside cells are released when cells die and their plasma membranes
become leaky. Our lab previously found that, in mammals, one such
molecule is actin. As actin has been highly conserved throughout
evolution, we wanted to know whether it can serve as a signal for
tissue damage in simpler organisms such as Drosophila and whether
the latter is a useful model to study sterile inflammation."
The researchers injected Drosophila with purified actin and saw
signs of systemic inflammation. They showed that this response
depends on activation of a signaling pathway called JAK/STAT, which
was already known to be induced in response to a range of different
stresses, all of which are likely to result in cell death.
Although some parts of the actin-sensing machinery are different
in flies and mammals, there seems to be a common need to detect
extracellular actin, which indicates that this pathway is
important. The research also showed that other parts of the
signaling machinery are essentially the same in flies and
mammals.
Professor Reis e Sousa says: "Extracellular actin has been
observed in clinical settings including acute respiratory distress
syndrome, Alzheimer's, rheumatoid arthritis, cystic fibrosis, among
others. Our data indicate that extracellular actin could instigate
inflammatory responses in these situations and exacerbate disease.
Therefore limiting the availability of actin in circulation might
help alleviate these damaging immune responses. This is an idea
that we are now investigating."
Another next step is identifying the receptor that detects actin
in Drosophila. This will allow scientists to assess the
contribution of released actin to various diseases and to find
orthologues, or genes with the same function, in mammals, including
humans.
The paper, Actin is an evolutionarily-conserved
damage-associated molecular pattern that signals tissue injury in
Drosophila melanogaster, is published in eLife.