Study reveals a control center for skin inflammation

Study reveals a control center for skin inflammation

Inflammatory reactions in the skin can reduce damage from UV radiation or infections, but can also lead to painful symptoms such as sunburn. A current study by the University of Bonn and the University Hospital of Bonn has now identified a molecular control that integrates these stress signals. The results were published in the Journal of Experimental Medicine.

As the largest organ in the human body, the skin literally represents a major barrier to environmental irritants and pathogens. When this barrier is compromised, painful inflammation can occur - as anyone who has ever been sunburned knows. But exactly how this is triggered has not yet been understood in detail. “In our study, we took a closer look at the processes,” explains Prof. Dr. Florian Schmidt, who leads a research group at the Institute for Innate Immunity at the University Hospital of Bonn.

UV stress triggers a signaling chain

UV light is very high in energy. Therefore, when it hits the skin, it can damage important cell molecules and, as a common result, trigger inflammation. However, exactly how this happens was unclear. “We have now been able to show that a known cellular stress signaling pathway can trigger these inflammatory reactions,” 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 according to the instructions in the genetic material. If this is impaired by UV damage, they sound the alarm: they trigger the so-called ribotoxic stress reaction. It has been known for years that this triggers a signaling cascade that leads to 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. These complex molecular machines can, among other things, convert inactive inflammatory messengers into their active form. At the same time, they ensure that numerous holes are created in the cell membrane. This allows messenger substances to escape to the outside and thus call the body's own defenses to help. Ultimately, the holes lead to the death of the cell: at some point it literally explodes and empties its contents into the tissue. The molecules suddenly released from inside the cells are another warning signal for the immune system.

Viruses also activate p38

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Interestingly, p38 is not only activated by excessive sunbathing. “We were able to show that mosquito-borne viruses can also activate NLRP1 via p38,” emphasizes Lea-Marie Jenster, doctoral student in the Schmidt laboratory and first author of this study. “This includes, for example, the chikungunya virus, which is a major problem in parts of Africa and Asia and could also reach Germany as a result of climate change.” Viruses probably even trigger the activation of p38 via several pathways.

P38 is a molecular information hub in the skin in which various warning signals converge - similar to the fire department's control center. However, not every incoming call for help immediately triggers the accumulation of inflammasomes – this only happens when the number and intensity of alarms exceed a certain threshold.”

Prof. Dr. Florian Schmidt, University of Bonn

This regulation is important because inflammasomes are dangerous weapons that cause significant collateral damage. For example, the severe inflammation caused leads to parts of the skin tissue dying.

However, sometimes inflammasomes are not combated rigorously enough - as with sunburn or some autoimmune diseases. Perhaps p38 opens up a new opportunity to specifically suppress such excessive immune reactions in the skin.

Participating institutions:

In addition to the University Hospital of Bonn and the University of Bonn, the University of Melbourne (Australia) and the Boston Children's Hospital (USA) were involved in the study.

Source:

University of Bonn

Reference:

Jenster, L.M., et al. (2022) P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and viral infection. Journal of Experimental Medicine. doi.org/10.1084/jem.20220837.

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