Researchers at the Cells-in-Motion Cluster of Excellence have decoded a mechanism found at the beginning of almost every inflammatory response. Their study provides a new approach to develop novel treatment options for many inflammatory disorders with many fewer side effects compared to current drugs.
In the body, the immune system often begins its response to various attackers in the same way: the body activates immune cells, so-called phagocytes, which migrate to sites of inflammation caused by, for example, foreign pathogens or damaged tissue. There, the phagocytes release certain proteins, including the S100A8/S100A9 heterodimeric protein complex, which triggers or amplifies the inflammatory reaction at the site of the disease.
However, if too many of these complexes are released, they can exacerbate the disease; for example, this happens in the case of autoimmune, rheumatic or dermatological diseases. Researchers at the Cells-in-Motion (CiM) Cluster of Excellence at the University of Münster have now decoded how the activity of these proteins is precisely regulated.
The leading scientists of the study, the immunologists Prof. Thomas Vogl and Prof. Johannes Roth, now want to use these novel fundamental insights to develop new treatment options to combat autoimmune diseases, arthritis, allergies or inflammatory diseases of the bowel, lung or cardiovascular system. The study was published in the "Journal of Clinical Investigation".
The detailed story
Many scientific publications have already described the tasks of the two proteins S100A8 and S100A9. But so far, it has not been clear to researchers whether these two proteins acted alone or in conjunction with each other. The Münster researchers have now been able to show that the proteins always work as a heterodimeric protein complex composed of both S100A8 and S100A9; in other words, a complex where both proteins are firmly associated. As soon as it is released, the heterodimer complex binds to a TLR4-expressing cell, triggering a suitable immune response via this receptor
. Importantly, the S100A8/S100A9 heterodimer complex only has a short life time to spark this initial impulse: If it does not find a suitable target cell for activation, two individual heterodimers associate to form a heterotetramer; in this form, each heterodimer complex is inactive. This mechanism guarantees that the body will only trigger an immune reaction where needed – in other words, the inflammatory reaction remains localized.
The researchers also showed that as soon as this regulation is disturbed so not all of the excess S100A8/S100A9 heterodimer complexes can form tetramers, the result is an exacerbation of disease: "Too many heterodimers remain active, trigger a strong immune response and act systemically in the entire body", explains Prof. Thomas Vogl, the lead author of the study. This is a process that is, for example, behind blood poisoning – but it is also relevant for many autoimmune diseases, rheumatoid arthritis, allergies, inflammatory skin diseases and even cardiovascular diseases.
Developing new treatment options with ideally no side effects
These findings by the Münster immunologists may lead to new approaches for treating many inflammatory diseases. Currently, new drugs are already being used to totally block the TLR4 receptor signaling pathway to inhibit misguided immune responses. However, one problem is that sometimes the body has to combat bacteria at the same time. As the immune system is blocked, the TLR4 receptor can no longer fulfill this important function anymore.
"This is why we’re searching for antibodies which specifically only block the S100-TLR4 axis, while the receptor is untouched, respectively free on the bacterial side", says Thomas Vogl. "These antibodies should specifically block only the active heterodimers and, in the following, weaken the immune reaction only locally, at the site of inflammation.
The TLR4 receptor, which is important for immune defense, remains untouched and can trigger the suitable immune response in the case of any bacterial danger." Drugs developed according to this new approach to treat, for example, autoinflammatory disorders would therefore have far fewer side effects for patients than currently existing pharmaceuticals.
The next step for the researchers is to work together with companies to find suitable antibodies and develop pharmaceuticals for treating diseases accompanied by overwhelming immune reactions. The first patents have already been applied for. It will take years, however, before drugs are available to deactivate excess S100A8/S100A9 in the human body and thus prevent unwanted immune reactions.
The study is the result of interdisciplinary collaborations between five different CiM laboratories. "Without the expertise and the help of all other involved researchers, we would not have been able to elucidate these interesting results", says Thomas Vogl. The Münster molecular biologists Dr. Athanasios Stratis and Dr. Viktor Wixler, for example, investigated genetically modified mice necessary for the study. The nuclear physicians Prof. Michael Schäfers and Dr. Sven Hermann contributed their expertise in imaging, enabling researchers to visualize the distribution of the S100 proteins in mice.
The study was funded by the Cells-in-Motion Cluster of Excellence and the Interdisciplinary Center for Clinical Research of the University of Münster. Financial support also came from the German Research Foundation through the Collaborative Research Centre 1009 "Breaking Barriers" at Münster University and through the "ImmunoSensation" Cluster of Excellence in Bonn. The German Federal Ministry of Education and Research also provided financial support.
Original publication (DOI: 10.1172/JCI89867)
Vogl T, Stratis A, Wixler V, Voller T, Thurainayagam S, Jorch SK, Zenker S, Dreiling A, Chakraborty D, Frohling M, Paruzel P, Wehmeyer C, Hermann S, Papantonopoulou O, Geyer C, Loser K, Schafers M, Ludwig S, Stoll M, Leanderson T, Schultze JL, Konig S, Pap T, Roth J. Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation. J Clin Invest 2018;128: 1852-1866.
https://www.jci.org/articles/view/89867 - Original publication
https://www.uni-muenster.de/Cells-in-Motion/de/people/all/roth.php - Prof. Johannes Roth
Sibylle Schikora | idw - Informationsdienst Wissenschaft
Study reveals how bacteria build essential carbon-fixing machinery
09.07.2020 | University of Liverpool
Stress testing 'coral in a box'
09.07.2020 | University of Konstanz
New insight into the spin behavior in an exotic state of matter puts us closer to next-generation spintronic devices
Aside from the deep understanding of the natural world that quantum physics theory offers, scientists worldwide are working tirelessly to bring forth a...
Kiel physics team observed extremely fast electronic changes in real time in a special material class
In physics, they are currently the subject of intensive research; in electronics, they could enable completely new functions. So-called topological materials...
Solar cells based on perovskite compounds could soon make electricity generation from sunlight even more efficient and cheaper. The laboratory efficiency of these perovskite solar cells already exceeds that of the well-known silicon solar cells. An international team led by Stefan Weber from the Max Planck Institute for Polymer Research (MPI-P) in Mainz has found microscopic structures in perovskite crystals that can guide the charge transport in the solar cell. Clever alignment of these "electron highways" could make perovskite solar cells even more powerful.
Solar cells convert sunlight into electricity. During this process, the electrons of the material inside the cell absorb the energy of the light....
Empa researchers have succeeded in applying aerogels to microelectronics: Aerogels based on cellulose nanofibers can effectively shield electromagnetic radiation over a wide frequency range – and they are unrivalled in terms of weight.
Electric motors and electronic devices generate electromagnetic fields that sometimes have to be shielded in order not to affect neighboring electronic...
A promising operating mode for the plasma of a future power plant has been developed at the ASDEX Upgrade fusion device at Max Planck Institute for Plasma...
07.07.2020 | Event News
02.07.2020 | Event News
19.05.2020 | Event News
09.07.2020 | Physics and Astronomy
09.07.2020 | Power and Electrical Engineering
09.07.2020 | Physics and Astronomy