Neutrophil granulocytes comprise important defences for the immune system.
When pathogenic bacteria penetrate the body, they are the first on the scene to
mobilise other immune cells via signal molecules, thereby containing the risk.
To this end, they release serine proteases – enzymes that cut up other proteins
to activate signal molecules. Scientists at the Max Planck Institute of
Neurobiology in Martinsried have now discovered a new serine protease:
neutrophil serine protease 4, or NSP4. This enzyme could provide a new target
for the treatment of diseases that involve an overactive immune system, such as
rheumatoid arthritis.
The functioning of the immune system is based on the complex interplay of the
most diverse cells and mediators. For example, neutrophil granulocytes (a group
of specialized white blood cells) react to bacteria by releasing substances
called serine proteases. These enzymes are able to activate signal molecules,
such as the chemokines, by cleaving them at a specific position on the molecule.
The active signal molecules then guide other immune cells to the focus of
inflammation in order to destroy the pathogens.
A research team led by Dieter Jenne at the Max Planck Institute of
Neurobiology in Martinsried has come across a previously unknown protease in
humans: neutrophil serine protease 4, or NSP4. "The special thing about this
enzyme is that it cuts proteins that have the amino acid arginine at a
particular point", says Dieter Jenne, research group leader at the
Martinsried-based Institute. "This is where NSP4 differs from the other three
known neutrophil serine proteases, which are similar in molecular structure, but
have a different recognition motif." The scientists may be able to harness this
difference to develop an active substance that specifically inhibits NSP4,
thereby reducing the immune reaction.
However, serine protease activity comes at a cost. The enzymes not only heal
inflammations, but sometimes cause them in the first place. If too many immune
cells are activated, they can use their arsenal of aggressive chemical weapons
against the body's own tissues. A number of chronic inflammatory diseases are
based on precisely this effect. As a result, scientists are searching for
substances that can block the neutrophil proteases. To date, however, none of
the substances tested have been developed into effective drugs.
"So far, we don't know the identity of the NSP4 substrate, but we assume they
must be signal molecules", says Dieter Jenne. Activated chemokines can recruit a
vast number of neutrophils, and their sheer quantity alone is enough to cause
tissue damage. "Proteases sometimes act as accelerants and can even trigger a
chronic inflammation quite independently of bacterial intruders. If we dampened
down the defences, we could counteract this effect", explains the scientist.
In terms of evolutionary history, NSP4 is the oldest of the four known
neutrophil serine proteases. Using gene sequences, scientists have shown that
the enzyme has hardly changed through hundreds of millions of years of evolution
from bony fish to humans. "That would indicate that NSP4 regulates a fundamental
process", says Dieter Jenne.
The fact that the enzyme remained undiscovered until now is because it occurs
at a much lower concentration than the other three proteases. The Max Planck
scientists came across it while searching the human genome for genes that encode
serine proteases. In the process, they noticed a previously unknown gene
sequence. Natascha C. Perera, a member of the Martinsried research group and
lead author of the study, managed to produce and examine the enzyme in its
active, folded state.
If they are to establish NSP4 in the future as a possible target protein for
anti-inflammatory drugs, the scientists must now examine its function in living
organisms and discover whether blocking the enzyme has adverse effects. The
scientists are working with the company Novartis to answer these questions in
laboratory mice. "NSP4 inhibitors could be used in diseases like chronic
arthritis or inflammatory skin diseases", says Dieter Jenne, "but first we have
to test the long-term effects of these substances."
**Published in "SCIENCE DAILY"
