Scientists at UC San Diego (UCSD) have uncovered what appears to be a crucial biochemical link between diabetes and eczema, previously thought to be two completely unrelated diseases. The researchers report that caspase 8, a protein previously linked only to cell death, plays a critical role in the healing of wounds in laboratory mice. The protein is deficient in humans with eczema, but produced in excess amounts by diabetics.
But the team wondered how caspase 8, which resides in cells at the surface of the epidermis, could account for this condition when the stem cells responsible for the proliferation phase are deeper in skin tissue and the infection-fighting cells in the blood vessels responsible for the inflammation phase are even deeper.
“What we discovered was that the loss of caspase 8 in the epidermis releases interleukin 1-a, which can travel deeper into the tissue to recruit immune cells and cause the local reservoirs of stem cells in the skin to start proliferating. This is the first time anyone has demonstrated that caspase 8 triggers the release of this protein and how it does so.”
The discovery, which appears in the March 26 issue of the journal Nature may clarify why many diabetics lack a normal wound response and suffer serious complications from trivial cuts and scrapes, and also explain why those with eczema exhibit a chronic inflammation of the skin that compromises its protective function.
“Not only does the loss of caspase 8 stimulate inflammation, which brings in a rush of cells designed to stop microbes from infecting the wound,” said Colin Jamora, Ph.D., assistant professor of biology at UCSD, “But it also stimulates the production of stem cells that provide the materials to help close the wound. That’s important, because in the initial stages of a wound the protective barrier provided by the skin is broken and the internal body is exposed to microbes and environmental toxins.”
The group made the surprise discovery when examining a mutant mouse that had been genetically engineered with unusually thick skin for a separate study that knocked out the gene in the epidermis necessary for the production of caspase 8.
The researchers initially suspected that the reason for the unusually thick-skinned mutant mouse was that the lack of caspase 8 in the epidermis was somehow interfering with the death program of the skin cells, leading to an accumulation of skin cells that should have otherwise died. “But what was actually happening was not that the skin cells were living longer, but that the lack of caspase 8 was stimulating more skin cells to divide, which was unexpected,” says Dr. Jamora. “And when we looked further, we also found that there was inflammation going on in the skin of these mice. Those two things led us to suspect that the loss of caspase 8 can trigger a normal wound-healing response in the absence of any trauma to the skin.”
The team is now studying laboratory mouse models of human diabetes, which produce excess amounts of caspase 8, to determine if artificially damping their production of caspase 8 will restore their ability to heal wounds.
“We are also using the caspase-8 knockout mouse as a model system to study eczema in order to identify the players that contribute to this disorder,” says Dr. Jamora.