Skin inflammation control centers are found

As the largest organ in the human body, the skin does provide a major barrier
to exposure to environmental stimuli and pathogens.
If this barrier is broken, painful inflammation will intensify – as anyone who has been sunburned
knows.
But until now, it was unclear how this was triggered
.
"In our study, we looked closely at the relevant processes," explains
Professor Florian Schmidt, who leads a research group at the Institute for Innate Immunology at the University Hospital Bonn.

UV pressure triggers the signal chain

Ultraviolet light has a high
energy.
Therefore, when it comes into contact with the skin, it destroys important cell molecules, triggering inflammation as a common consequence
.
However, it's unclear exactly how this happened
.
"We have now been able to demonstrate that a known cellular stress signaling pathway can trigger these inflammatory responses," explains Schmidt, who is also a member of
the Interdisciplinary Research Area (TRA).
"Life and Health" and the Cluster of Excellence in
Immunosensation at the University of Bonn.

The cell's own "engineering office," the ribosome, normally assembles proteins
according to instructions in the genetic material.
When this ability is impaired by UV damage, they sound the alarm: they trigger the so-called nuclear toxic stress response
.
For years, it has been known that this causes a signaling cascade that leads to the activation
of an enzyme called p38.
"Our study shows that the p38 molecule modifies NLRP1, a key switch for skin inflammation, to activate it
in a new way.
This initiates the assembly
of inflammasomes consisting of many molecules.
”

Inflammasomes are powerful weapons
of the innate immune system.
In addition to this, these complex molecular machines can convert inactive messenger substances of inflammation into active forms
.
At the same time, they ensure the formation of a large number of pores
on the cell membrane.
This allows the messenger matter to reach the outside world, calling on the body's own defenses to help it
.
Eventually, these cavities cause cell death: at some point, it actually explodes, draining its contents into the tissue
.
These sudden release of molecules from the cells is another warning sign
for the immune system.

The virus also activates p38

Interestingly, p38 is not only activated
when it is exposed to excessive sun exposure.
"We were able to show that mosquito-borne viruses can also activate NLRP1 via p38," emphasizes Lea-Marie Jenster
, a PhD student in Schmidt's lab and lead author of the study.
"For example, chikungunya virus is a major problem in parts of Africa and Asia, and it could also spread to Germany
after climate change.
" The virus may even trigger the activation
of p38 in several different ways.

Schmidt explains: "P38 is the molecular information hub in the skin, where various alarm signals converge – similar to the control center
of a fire department.
" "However, not every distress signal immediately triggers the aggregation of inflammasomes – this only happens
when the number and intensity of alarms exceed a certain threshold.
" This regulation is important because inflammasome bodies are dangerous weapons that cause considerable collateral damage
.
For example, intense inflammation can lead to the death of parts of the
skin tissue.

However, sometimes the control of the inflammasome is not tight enough – such as sunburn or some autoimmune diseases
.
Perhaps p38 opens up a new possibility to specifically suppress such a vigorous immune response
in the skin.

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

Journal Reference:

1. 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, Stefan Ebner, Dorothee J.
   Lapp, Jacob Mayer, Jonas Moecking, Hidde L.
   Ploegh, Eicke Latz, Felix Meissner, Matthias Geyer, Beate M.
   Kü mmerer, Florian I.
   Schmidt.
   P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection.
   Journal of Experimental Medicine, 2023; 220 (1) DOI: 10.
   1084/jem.
   20220837