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11/02/2022 09:12

Control hub for skin inflammation discovered

Svenja Ronge Dezernat 8 - Hochschulkommunikation
Rheinische Friedrich-Wilhelms-Universität Bonn

    Inflammatory reactions in the skin can reduce damage from UV radiation or infections, but can also result in painful symptoms such as sunburn. A recent study at the University of Bonn has now identified a molecular control which integrates these stress signals. The results have been published in the Journal of Experimental Medicine.

    As the largest organ of the human body, the skin literally provides a major barrier exposed to environmental stimuli and pathogens. Painful inflammation can be mounted if this barrier is compromised – as anyone who has ever had a sunburn knows. But exactly how this is triggered was not understood in detail until now. "In our study, we took a closer look at the processes involved," explains Prof. Dr. Florian Schmidt, who heads a research group at the Institute of Innate Immunity at the University Hospital Bonn.

    UV stress triggers signal chain

    UV light is very high in energy. When it hits the skin, it can therefore damage important cellular molecules, sparking inflammation as a common consequence. However, it was unclear how this exactly happens. "We have now been able to show that a known cellular stress signaling pathway can trigger these inflammatory responses," explains Schmidt, who is also a member of the Transdisciplinary Research Area (TRA) "Life and Health" and the ImmunoSensation2 Cluster of Excellence at the University of Bonn.

    The cell's own "engineering offices," the ribosomes, normally assemble proteins based on the instructions in the genetic material. When this is impaired due to UV damage, they sound the alarm: They trigger the so-called ribotoxic stress response. It has been known for years that this causes a signaling cascade resulting in the activation of an enzyme called p38. "Our research shows that p38 molecularly modifies NLRP1, a critical switch for inflammation in the skin, and thus activates it in a novel way. This initiates the assembly of inflammasomes from many molecular building blocks."

    Inflammasomes are powerful weapons of the innate immune system. Among other things, these complex molecular machines can convert inactive messenger substances for inflammation into their active form. At the same time, they ensure that numerous holes are formed in the cell membrane. This allows messenger substances to reach the outside and thus call the body's own defense forces to its aid. Ultimately, the holes lead to the death of the cell: At some point, it practically explodes and empties its contents into the tissue. The molecules that are now abruptly released from within the cell are another warning sign for the immune system.

    Viruses also activate p38

    Interestingly, p38 is not only activated by excessive sunbathing. "We were able to show that mosquito-borne viruses can activate NLRP1 through p38 as well," emphasizes Lea-Marie Jenster, a PhD student in the Schmidt lab and the lead author of this study. "These include, for instance, chikungunya virus, which is a major problem in parts of Africa and Asia and could also reach Germany in the wake of climate change." Viruses probably even trigger the activation of p38 via several different pathways.

    "P38 is a molecular information hub in the skin, in which various warning signals converge - similar to the fire department's control center," Schmidt explains. "However, not every incoming call for help immediately triggers the assembly of inflammasomes - this only happens when the number and intensity of alerts exceed a certain threshold." This regulation is important, since inflammasomes are dangerous weapons which cause considerable collateral damage. For example, the strong inflammation that is triggered causes parts of the skin tissue to perish.

    Sometimes, however, inflammasomes are controlled not strictly enough - as in the case of sunburn or even some autoimmune diseases. Perhaps p38 opens up a new possibility to specifically suppress such exuberant immune reactions in the skin.

    Participating institutions and funding:
    In addition to the University Hospital of Bonn and the University of Bonn, the University of Melbourne (Australia) and Boston Children's Hospital (USA) were involved in the study. The work was funded by the German Research Foundation (DFG) and the Klaus Tschira Boost Fund.


    Contact for scientific information:

    Prof. Florian I. Schmidt
    Institute of Innate Immunity, University of Bonn
    Email: fschmidt@uni-bonn.de
    Tel. Office: +49-228/287-51124
    Tel. Lab: +49-228/287-54708
    mobile: +49-176/70021810


    Original publication:

    Lea-Marie Jenster, Karl-Elmar Lange, Sabine Normann, Anja vom Hemdt, Jennifer D. Wuerth, Lisa D.J. Schiffelers, Yonas M. Tesfamariam, Florian N. Gohr, Laura Klein, Ines H. Kaltheuner, Dorothee J. Lapp, Jacob Mayer, Jonas Moecking, Hidde L. Ploegh, Eicke Latz, Matthias Geyer, Beate M. Kümmerer, Florian I. Schmidt: P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection; Journal of Experimental Medicine; https://doi.org/10.1084/jem.20220837


    Images

    In human skin cells, inflammasomes (green) are assembled as a result of a ribotoxic stress response. Later, red dye flows into the cell through the "holes" that these create.
    In human skin cells, inflammasomes (green) are assembled as a result of a ribotoxic stress response. ...
    AG Schmidt
    AG Schmidt / University of Bonn


    Criteria of this press release:
    Journalists
    Biology, Medicine
    transregional, national
    Research results, Scientific Publications
    English


     

    In human skin cells, inflammasomes (green) are assembled as a result of a ribotoxic stress response. Later, red dye flows into the cell through the "holes" that these create.


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