‘Growing end’ of inflammation discovered: How the danger sensor NLRP3 lengthens itself like a thread

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 were able to show that inflammatory reactions of an important sensor protein continue in a specific spatial direction. This finding has the potential to possibly stop inflammation at the “growing end” and thus stop chronic inflammatory diseases. The study has now been published in the journal “The progress of science. “

If bacteria or viruses attack living cells or other foreign substances appear in them, the danger sensor is activated with the abbreviation NLRP3. “The protein deposits in the brain that are characteristic of Alzheimer’s disease, the so-called amyloid-ß plaques, can also set NLRP3 in motion,” says prof. Dr Matthias Geyer from the Institute of Structural Biology at Bonn University Hospital, with reference to previous studies. As these previous studies by researchers show, this reaction provides more and more energy: The inflammatory reaction triggered by NLRP3 promotes further deposition of amyloid-ß plaques and contributes significantly to the disease process.

Once activated, several NLRP3 proteins attach to each other, thus forming the core of a filamentous structure in which more and more proteins accumulate. “The reaction starts as soon as a dozen of the NLRP3 molecules are present,” Geyer reports. In theory, an infinite number of NLRP3 molecules can coalesce and extend the wire-like structure – scientifically called “filament” – longer and longer. No Hochheiser from Prof. Geyer’s team has now been able to show in which direction this filament is growing and continues to expand. “We were able to obtain these insights using cryoelectron microscopy. This method makes it possible to observe protein molecules with up to 80,000 times magnification and thus make them directly visible,” says Hochheiser.

“Still image” of the wire-like structure under the microscope

In small steps, the researcher dropped NLRP3 isolated from cells on a sample carrier and quick-frozen this mixture. This gave the researchers a kind of “still image” under the cryoelectron microscope. Thus, the emerging wire-like structure of NLRP3 molecules arranged side by side was visualized. “These individual images made it possible to understand how the filaments are elongated, just like in a movie,” says Hochheiser. Because the molecules fall differently on the sample carrier during drizzle, they can be seen from different perspectives under the microscope. These different views can be combined on the computer to create a three-dimensional image. The results showed that the filaments are only formed in one direction. “This made it possible for us to visualize part of the inflammatory apparatus and literally read the direction of growth,” says prof. Geyer, who led the study and is a member of the Cluster of Excellence ImmunoSensation2 and the transdisciplinary research area “Life and Health” at the University of Bonn.

Stop chronic inflammatory diseases

“The technical challenge was to find the transitions in the wire-like structures and make them visible in the image,” says prof. Dr. Elmar Behrmann from the Institute of Biochemistry at the University of Cologne. “The new findings now allow us to target the growing part of the inflammatory response with the help of antibodies or drugs,” Hochheiser explains. This brings the researchers closer to their goal of stopping the continued build-up of the inflammation apparatus and thus counteracting chronic inflammation.

Participating institutions and funding:

In addition to the Institute of Structural Biology and the Institute of Innate Immunity at Bonn University Hospital, the Institute of Biochemistry at the University of Cologne and The Walter and Eliza Hall Institute of Medical Research in Melbourne (Australia) are involved in the study. Measurements were performed 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 Kröner-Fresenius Foundation and the German Research Foundation.

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