Uncovering the role of caspase-8 in mouse skin cells may contribute to a better understanding of human diseases involving chronic skin inflammation, such as psoriasis.
The organism's first line of defense, which isolates it from the environment and protects it from disease-causing bacteria and viruses, is a thin and hard layer of dead cells that cover the epidermis - the outer part of the skin. These cells are born in a lower layer of the skin, and changes that occur in them cause them to migrate to the surface, and die there. A new study by an international team of scientists, led by Prof. David Welch from the Department of Biological Chemistry at the Weizmann Institute of Science, shows that this desired death also carries the seeds of a disease. It turns out that the enzyme caspase-8 - discovered in Prof. Welch's laboratory - which is involved in the mechanisms of cell death, plays another important role in curbing the inflammatory process that occurs as a result of the death of skin cells. Abnormal activity of this enzyme may cause the development of chronic dermatitis.
Cell death is an essential process for the normal functioning of the body. So essential, that a kind of "software" for self-destruction called apoptosis is "installed" in the cells. Apoptosis is necessary both for the growth and renewal of the body and for preventing the development of diseases, such as cancer. About a decade ago, Prof. David and Lech and his group members discovered the enzyme caspase-8, a member of the caspase enzyme family. Like other members of this family, caspase-8 plays a central role in apoptosis, but several other roles are also reserved for it - as Prof. Welch and the members of his research group have proven over the years. When Prof. Valch, together with Dr. Tai-Bong Kang, studied the roles of caspase-8 in different tissues of the body, several years ago, he noticed that in a certain tissue - the skin - the enzyme plays a very important role that is not related to cell death. However, the exact role of the enzyme in this tissue was unclear.
An international team of scientists from India, Korea, Germany and Israel participated in solving the mystery of the role that caspase-8 plays in the skin. Together with Dr. Uri Brenner from the Department of Veterinary Resources at the Institute, they developed mice that were genetically engineered in a special way: since preventing the formation of caspase-8 throughout the body causes the mice to die even before they are born, the scientists engineered animals that produced the enzyme in all tissues - except the skin. In addition, several other genes that may cause skin diseases were "deleted" from the genetic load of these mice - this in order to isolate the effect of caspase-8.
In the first step, the scientists wanted to check whether it is possible that caspase-8 still fulfills its well-known role - cell death - in the upper layer of the skin. It turned out that the skin cells of the genetically engineered mice, which did not include the enzyme, committed suicide exactly "according to the book" and according to the plan. However, three days after the birth of the transgenic mice, signs of severe skin disease appeared in them. The researchers concluded that caspase-8 is not essential for the production of the layer of dead cells in the skin, and asked to check why a lack of this enzyme causes the disease, and how it is formed. Does the disease break out as a result of a process taking place inside the cell, or perhaps some external factor - a bacterium, or a faulty immune cell - is what ignited the inflammation? The findings of the team of scientists showed that changes that occur inside the skin cell, at the time it dies and moves to the outer layer, are the causes of inflammation. That is, while in other cases caspase-8 causes the death of cells, in the case of skin development its role is to prevent the inflammatory process that occurs following cell death.
Later, the researchers discovered that it is a pattern of inflammation that developed during evolution to meet a vital need: in normal situations, it is the body's response to the invasion of disease-causing viruses. Symptoms such as fever, redness, swelling and other signs of inflammation are all part of a strategy the body uses to fight various invaders, especially viruses. The role of caspase-8 in the skin is to restrain the activity of a molecule called IRF3, which dictates the production of interferon and other proteins that increase the antiviral response. It is not clear why the body chose to induce constant activation of IRF3 in the skin, as this strategy carries the risk of chronic inflammation. Scientists believe that it gives an advantage because it allows "high alertness" against an attack on the first line of defense, which is the skin.
The research was led by Dr. Andrew Kovalenko in Prof. Welch's laboratory. The research student at the time, Jin-Chul Kim, focused on characterizing the role of the enzyme in the epidermis. The post-doctoral researchers, Dr. Akhil Rajput and Dr. Konstantin Bogdanov, investigated the molecular mechanisms, and Dr. Tae-Bong Kang continued the research by examining the role of the enzyme in the body and examining the ways that allow it to cause cell death in certain situations, and inhibit inflammation in certain situations others. Two German scientists, Dr. Michael Kracht from the Rudolph-Buchheim Institute of Pharmacology in Giessen, and Dr. Oliver Dietrich-Breiholz from the Medical School in Hanover, assisted in the analysis of gene expression in the skin.
The research findings were published in The Journal of Experimental Medicine.
Uncovering the role of caspase-8 in mouse skin cells may contribute to a better understanding of human diseases involving chronic skin inflammation, such as psoriasis. The similarity between these two conditions is expressed, among other things, in that blocking the function of TNF - another protein studied in Velach's laboratory, which forms the basis of a highly successful drug against psoriasis - causes the symptoms of the skin disease to be alleviated in the transgenic mice. "In addition," says Prof. Velach, "our previous studies indicate the possibility that similar processes take place in other organs of the body. It is possible that the caspase-8 enzyme is essential for preventing inflammation, and that its abnormal activity may be related to a number of chronic inflammatory diseases."
