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Pathogens of exceptional shape:

How crystals cause chronic inflammation

Munich, 07/21/2008

When it comes to pathogens, those who think only of bacteria, viruses and other parasites are forgetting at least one important category: crystals can be implicated in medical conditions, too. The ‘black lung’ (silicosis) from which miners suffer, for example, is triggered by quartz sand, while uric acid crystals in the joints cause gout. Crystalline structures even play a part in neurodegenerative Alzheimer’s disease.  In all of these cases, the body responds with chronic inflammation. An international team of researchers, one of whom is LMU medical scientist Franz Bauernfeind, has now recently described the molecular mechanism underlying this  defensive response. “Irrespective of structural details, all crystals induce a similar immune response,” reports Bauernfeind. “And the protein NALP3 is always significantly involved, because it acts as an universal danger receptor. This protein will be an important molecule to target in future pharmacological research, as it plays an important role in the induction of inflammation.” (online, Nature Immunology)

A crystal can probably best be described as perfectly formed. In the ideal crystal, after all, identical units are evenly arranged as if in a three-dimensional lattice. This applies just as much to ice crystals and salt crystals as it does to many gemstones. One important example here is quartz, which, as a rock crystal, is mostly made up of silicon dioxide (silica). If there are chemical impurities present, then you get coloured variants such as amethyst or citrine. But quartz is also a component of porcelain and other products, which means that professional gemstone cutters, miners and workers in the ceramics industry and a number of other professions are exposed to crystalline silica. This substance can only be dangerous to them if inhaled, but inhalation poses the serious risk of silicosis. That is the ‘black lung’ disease, dreaded since ancient times, in which microcrystals deposit in the alveoli of the lungs, where they can’t be removed. The destroyed lung areas are replaced by granular connective tissue. Due to the increased scarring of the lungs, the body is no longer supplied with enough oxygen and the afflicted person runs the risk of various secondary disorders – including lung cancer – and ultimately death.

But there are other crystals aside from silica that can cause diseases. The extremely painful gout, for example, which can lead to kidney failure, arises when the metabolite uric acid deposits as crystals in the joints. The death of neurons in the brain of Alzheimer patients might be – at least in part – a result of tiny protein fragments that clump into a kind of crystal. “And yet, crystals in the form of aluminium salts have been used in vaccines for many decades,” reports Bauernfeind, one of the two first authors of the study. “They are employed as adjuvants, which means they are supplied to support the effect of the vaccine. The crystalline substance, alum, is still the only adjuvant that the American FDA has approved for human vaccines – even though its mechanism of action has never been understood until now.”

This gap in knowledge, however, has now been closed. We know already that crystals and similar structures cause a massive inflammatory reaction in the organism. “But only now have we been able to describe what molecular mechanisms trigger this,” states Bauernfeind. “We can demonstrate that crystal-induced inflammations can be tracked down to the release of a certain immune factor, the messenger interleukin-1. The body responds to all crystals in the same way, independently of their specific structure.” These structures – whether crystalline materials or aggregated proteins – are taken up by immune cells as part of the body’s immune response. However, the cells’ attempt to break down these foreign substances inside certain organelles, the phagolysosomes, most often fails. Because the body cannot eliminate the foreign crystalline substances, the result is chronic inflammation. It follows that the crystalline adjuvant in vaccines could also trigger a stronger – and in this case desired – immune response, thus leading to greater success of the vaccine.

Thanks to the new results, it is now clear which molecular mechanisms trigger crystal-induced inflammation: the crystals in the phagolysosomes cause damage to the cellular subunits. This results in leakage and access of protein-degrading enzymes to the cell’s cytoplasm. For the body, this is a universal danger signal, which it responds to with an inflammation. The enzyme cathepsin-B plays a central part in this response. And yet, the researchers have focussed their attention on another protein: NALP3 is a component of the inflammasome, a complex of several immune factors, which responds to unspecific dangers to the organism. The protein NALP3 plays a key role here: it recognizes the destroyed lysosomes as a danger signal and initiates the immune response. Over several intermediate steps, the inflammasome complex then activates the immune mediator interleukin-1, which even in small quantities leads to fever and other inflammatory reactions.

The project came about as a result of an international scientific discussion between the Department of Clinical Pharmacology of LMU Munich, under the direction of Professor Stefan Endres, and the workgroup of Professor Eicke Latz at the University of Massachusetts Medical School in Worcester, USA, where the practical work was carried out. For several years, members of the group have had the opportunity to perform tests in the partner laboratory, and learn new techniques. “Actually, I only intended to go to the USA for three months,” reports Bauernfeind. “But the project developed so promisingly that I stayed for a year. After all, we even succeeded in proving that NALP3 is a universal sensor of danger signals. This rather unspecific function makes the protein an especially interesting molecule to target in pharmacological research. It is a key factor in numerous inflammatory mechanisms. And more importantly, the chronic diseases caused by crystals are widespread diseases that still cannot be satisfactorily treated.”

 

Publication:
“Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization”,
Veit Hornung, Franz Bauernfeind, Annett Halle, Eivind O Samstad, Hajime Kono, Kenneth L Rock, Katherine A Fitzgerald  Eicke Latz,
Nature Immunology, online on 11 July 2008

Contact:
Franz Bauernfeind
Department of Clinical Pharmacology of Ludwig-Maximilian University (LMU) Munich
Tel.: ++49 (0) 89 / 5160 – 2378
Fax: ++49 (0) 89 / 5160 – 4406
E-Mail: franz.bauernfeind@med.uni-muenchen.de
Web: www.klinische-pharmakologie.de

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