Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Münster researchers have discovered a possible new treatment for regulating inflammation

05.06.2018

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.


Binding model: The S100A8/S100A9 protein complex (grey/beige) binds to the TLR4 receptor (rainbow-coloured) and MD2 (red) and triggers immune reactions in cells.

Vogl et al./ J. Clin. Invest.

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.

Funding

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.

Weitere Informationen:

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

More articles from Life Sciences:

nachricht OHIO professor Hla develops robust molecular propeller for unidirectional rotations
22.08.2019 | Ohio University

nachricht In cystic fibrosis, lungs feed deadly bacteria
22.08.2019 | Columbia University Irving Medical Center

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Physicists create world's smallest engine

Theoretical physicists at Trinity College Dublin are among an international collaboration that has built the world's smallest engine - which, as a single calcium ion, is approximately ten billion times smaller than a car engine.

Work performed by Professor John Goold's QuSys group in Trinity's School of Physics describes the science behind this tiny motor.

Im Focus: Quantum computers to become portable

Together with the University of Innsbruck, the ETH Zurich and Interactive Fully Electrical Vehicles SRL, Infineon Austria is researching specific questions on the commercial use of quantum computers. With new innovations in design and manufacturing, the partners from universities and industry want to develop affordable components for quantum computers.

Ion traps have proven to be a very successful technology for the control and manipulation of quantum particles. Today, they form the heart of the first...

Im Focus: Towards an 'orrery' for quantum gauge theory

Experimental progress towards engineering quantized gauge fields coupled to ultracold matter promises a versatile platform to tackle problems ranging from condensed-matter to high-energy physics

The interaction between fields and matter is a recurring theme throughout physics. Classical cases such as the trajectories of one celestial body moving in the...

Im Focus: A miniature stretchable pump for the next generation of soft robots

Soft robots have a distinct advantage over their rigid forebears: they can adapt to complex environments, handle fragile objects and interact safely with humans. Made from silicone, rubber or other stretchable polymers, they are ideal for use in rehabilitation exoskeletons and robotic clothing. Soft bio-inspired robots could one day be deployed to explore remote or dangerous environments.

Most soft robots are actuated by rigid, noisy pumps that push fluids into the machines' moving parts. Because they are connected to these bulky pumps by tubes,...

Im Focus: Vehicle Emissions: New sensor technology to improve air quality in cities

Researchers at TU Graz are working together with European partners on new possibilities of measuring vehicle emissions.

Today, air pollution is one of the biggest challenges facing European cities. As part of the Horizon 2020 research project CARES (City Air Remote Emission...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

The power of thought – the key to success: CYBATHLON BCI Series 2019

16.08.2019 | Event News

4th Hybrid Materials and Structures 2020 28 - 29 April 2020, Karlsruhe, Germany

14.08.2019 | Event News

What will the digital city of the future look like? City Science Summit on 1st and 2nd October 2019 in Hamburg

12.08.2019 | Event News

 
Latest News

OHIO professor Hla develops robust molecular propeller for unidirectional rotations

22.08.2019 | Life Sciences

127-year-old physics problem solved

22.08.2019 | Physics and Astronomy

Physicists create world's smallest engine

22.08.2019 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>