The epidermis, the upper layer of the skin, protects the body from external aggressions. To allow its renewal, the stem cells located in its deepest layer constantly produce keratinocytes. These new cells are gradually pushed towards the surface, differentiate and accumulate protein condensates. Arriving at the top of the epidermis, the keratinocytes undergo programmed death, cornification, to create a protective barrier of dead cells.
“The way the epidermis constantly renews itself is well documented. However, the mechanisms that drive this process remain partially unknown,” explains Gaby Palmer-Lourenço, associate professor at the Faculty of Medicine of the University of Geneva (UNIGE) and principal investigator of a study to be read in the journal “Cell Reports”.
Interleukin 38 (IL-38) is a small messenger protein that mediates communication between cells. It is known for its functions in the regulation of inflammatory responses. Its presence in keratinocytes was previously associated with its role in preserving the immune balance of the skin. “In keratinocytes in vivo, we discovered that IL-38 forms condensates, in other words specialized aggregates of proteins with precise biochemical functions, a behavior previously unknown for this protein,” says Gaby Palmer-Lourenço. Even more surprising, the closer the keratinocytes were to the surface, the more the quantity of IL-38 in these condensates increased.
Blood vessels stop in the skin layer below the epidermis. Therefore, the amount of oxygen available to keratinocytes is much lower in the lower layers than in the upper part of the epidermis, which is directly exposed to the oxygen present in the air around us. However, although it is necessary for the proper functioning of cells, oxygen also causes oxidative stress by forming free radicals, reactive molecules that endanger the cell.
“However, our laboratory experiments have shown that oxidative stress causes the creation of IL-38 condensates,” confirms Alejandro Díaz-Barreiro, post-doctoral student at the UNIGE Faculty of Medicine and first author of the study. . “Our results suggest that as we get closer to the surface of the epidermis, the increase in oxygen concentration promotes the formation of protein condensates, which then give the signal to keratinocytes that they are at good place to enter cell death,” continues Gaby Palmer-Lourenço.
This hypothesis provides new avenues for understanding the mechanisms of epidermis renewal. It could also open the way to a better understanding of the pathological mechanisms at the origin of certain skin diseases, such as psoriasis or atopic dermatitis. These questions will be evaluated by the research group in future work.
Alejandro Díaz-Barreiro is already working on the next step: “In the model we used until now, the effects of oxidative stress were artificially created in a single layer of keratinocytes, a scenario that differs from the real situation in the skin. We are therefore in the process of developing a new experimental system which makes it possible to expose reconstituted human epidermis in vitro to an oxygen gradient. In this model, only the surface of the epidermis will be in contact with the ambient air, while the other layers will be protected. We will thus be able to study in detail the effect of oxidative stress on the renewal of the epidermis.
By allowing more precise analysis of human cells, this new system will offer an alternative to animal models often used to study skin biology and diseases.
