Redness, swelling, pain – these are signs of inflammation. It serves to protect the body from pathogens or foreign substances. Researchers from the Universities of Bonn and Cologne have been able to show that inflammatory reactions of an important sensory protein proceed in a certain spatial direction. This discovery has the potential to stop inflammation at the “end of growth,” and thus stop chronic inflammatory diseases. The study is published in the journal »Advances in science».
When bacteria or viruses attack living cells or they have other foreign substances, the danger sensor with the abbreviation NLRP3 is triggered. “Protein deposits in the brain that are characteristic of Alzheimer’s disease, so-called amyloid-ß plaques, can also trigger NLRP3,” says Professor Dr. Matthias Geyer of the Institute of Structural Biology at Bono University Hospital, citing previous research. As these previous studies by researchers show, this reaction is increasingly self-feeding: the inflammatory response caused by NLRP3 contributes to the further deposition of amyloid ß plaques and makes a significant contribution to the disease process.
Upon activation, several NLRP3 proteins attach to each other and thus form the nucleus for a filamentous structure in which more and more proteins assemble. “The reaction begins as soon as about a dozen NLRP3 molecules are present,” Geyer said. Theoretically, an infinite number of NLRP3 molecules can bind together and expand a filamentous structure – scientifically called “filaments” – further and further. Inga Hochheiser of Professor Geyer’s team has now been able to show the direction in which this thread is growing and continuing to expand. “We were able to get these ideas through cryoelectron microscopy. This method allows us to observe protein molecules up to 80,000 times magnification and thus make them directly visible,” says Hochheiser.
“Still image” of filamentous structure under a microscope
In small steps, the scientist poured NLRP3, isolated from cells, onto the sample carrier and froze the mixture. This gave the researchers a kind of “still image” under a cryoelectron microscope. Thus, a new filamentous structure of NLRP3 molecules located nearby was visualized. “These individual images made it possible to understand how the threads lengthen, as in the film,” says Hochheiser. Because the molecules fall differently on the sample carrier when dropped, they can be seen from different points of view under a microscope. These different types can be combined on a computer to create a three-dimensional image. The results showed that the threads are formed in only one direction. “This allowed us to visualize part of the inflammatory apparatus and literally read the direction of growth,” says Professor Geyer, who led the study and is a member of ImmunoSensation2’s cluster of best practices and the Life and Health transdisciplinary research area at the University of Bonn.
Stopping chronic inflammatory diseases
“The technical challenge was to find transitions in the filamentous structures and make them visible in the image,” says Professor Dr. Elmar Berman of the Institute of Biochemistry at the University of Cologne. “The new findings now allow us to target a growing end to the inflammatory response with antibodies or drugs,” explains Hochheiser. This brings researchers closer to their goal – to stop the further growth of the inflammatory apparatus and thus resist chronic inflammation.
Participating institutions and funding:
In addition to the Institute of Structural Biology and the Institute of Innate Immunity of the University Hospital of Bonn, the study involved the Institute of Biochemistry of the University of Cologne and the Walter and Eliza Hall Institute for Medical Research in Melbourne (Australia). The measurements were carried out at the Caesar Research Center in Bonn and at the Rudolf Virchow Center at the University of Würzburg. The study was funded by the Else Kroner-Fresenius Foundation and the German Research Foundation.
Source of history: