People with diabetes, especially those with the type 1 form of the disease, are at increased risk of broken bones.
A key culprit seems to be a type of inflammation in the stem cells that are responsible for forming new bone. So a pair of University of Pennsylvania scientists tried a logical experiment in lab mice: blocking that inflammation to see whether the animals bones would be less fragile.
It worked, but something unexpected happened. The mice also developed scaly lesions on their skin.
It turned out that by blocking one type of inflammation, the researchers at Penns School of Dental Medicine had sent another into overdrive. The result was a skin condition called atopic dermatitis an often debilitating type of eczema that affects millions of people.
The finding could lead to better treatments for a condition that many struggle to keep in check, the authors reported this month in Science Translational Medicine, collaborating with researchers at Penn Medicines dermatology department and Oak Ridge National Laboratory, among other institutions.
In people with atopic dermatitis, the inflamed patches of skin are known to be a sign of an abnormal immune response. But to their surprise, the authors of the new study found that the initial trigger may come from skin cells that are not part of the immune system.
Its the opposite of what you would predict, said Dana Graves, a Penn Dental professor and one of the studys senior authors.
The primary role of these cells, called fibroblasts, is secreting collagen, which gives the skin its structure. Yet in the study, the scientists found that these cells also can secrete inflammatory signals called cytokines cousins of the proteins that the immune system produces in fighting infectious diseases such as COVID-19.
Both in the lab mice and in samples of human skin cells, the researchers found that with a bit of genetic wizardry, they could prompt fibroblasts to become dysregulated secreting high levels of a type of cytokine that would in turn recruit immune cells called eosinophils. These are useful disease-fighting cells in the right context but in this case, an apparent sign of an immune system out of control.
Peck Ong, a pediatric allergist-immunologist at Childrens Hospital Los Angeles who was not involved with the study, said further research in humans was needed before these findings could yield new treatments. Yet the study suggests physicians may need to think about this skin condition in a completely new way, he said.
This paper was very novel in terms of showing fibroblasts being a primary reason behind inflammation, he said. They showed that very convincingly.
At least 1 in 10 children develops atopic dermatitis, which is marked by itchiness and, in severe cases, an agonizing cycle of oozing, blistering, and crusting skin. Some children eventually grow out of it, but the condition persists for many into adulthood. And in some patients, it strikes for the first time in adulthood.
Steroid creams and other topical creams may provide temporary relief for some, but others must resort to periodic injections of customized antibodies to achieve relief. Such drugs cost thousands and are not covered by some insurers. They also can lead to unpleasant side effects.
The condition affects people of all skin colors, though physicians may sometimes underestimate its severity in Black patients and others with darker skin, Ong said.
The Penn study began more than five years ago, when Kang Ko, then a doctoral student in Graves lab at the dental school, was working with the diabetic mice. As dental researchers, they were drawn to the topic in part because diabetes can weaken bones in the jaw.
When Ko deleted a gene to block the inflammation that was thought to weaken the animals bones, the skin lesions started to appear a few weeks after they were born.
It had nothing to do with diabetes, as lesions also occurred when he blocked the inflammation in nondiabetic control animals.
It was quite confusing, said Ko, who has since become an assistant professor at the dental school. By deleting one gene, we were getting two very different responses based on what kind of tissue we were dealing with, bone and skin.
He and Graves wondered whether the lesions were a sign of cancer. They spent months trying to untangle how that might be occurring, looking for telltale signs in the animals bone marrow and spleen. No luck.
There were a lot of blind roads, Graves said.
Then Ko happened to attend a talk by John Seykora, a professor of dermatology at Penns Perelman School of Medicine. Ko and Graves enlisted Seykoras help, and the dermatologist identified the lesions as the mouse version of atopic dermatitis.
The team then brought in the Oak Ridge scientists, who used genetic sequencing equipment to identify which proteins were present in elevated levels in the mouse cells. The apparent culprits were a cytokine called CCL-11 and a protein transcription factor called CEBPB.
The team showed that these agents led to the recruitment of eosinophil cells, which in turn activated a type of immune agent called a helper T-cell.
Now comes the challenge of determining where to intervene in this complex cascade of events. Other scientists already have developed antibodies that inhibit CCL-11. But it is not clear if that cytokine would be the right target in treating atopic dermatitis, said Seykora, the dermatology professor.
In mice with the skin condition, this cytokine is clearly setting off an unwelcome tide of out-of-control inflammation somewhat like the storms of other cytokines that were blamed for dangerous inflammation in severe cases of COVID.
But any attempts to interfere with inflammation must be handled with care, as it plays a key role in activating the immune system against disease. In people whose fibroblasts behave this way, there is likely a genetic component, so the team is looking at other approaches to address the root cause of the problem, Ko said.
Were exploring some of the upstream events that could be blocked efficiently, he said.
Whats clear is that dermatologists need to think more broadly about how atopic dermatitis gets underway, Seykora said. Traditionally, it is thought to be triggered by dust mites or other antigens that penetrate the skin, prompting an inflammatory response from the immune systems T-cells.
As a result, patients often are counseled to use moisturizing cream to keep the skin barrier intact. Thats still a good idea, Seykora said.
But now it seems the inflammation may be triggered well before the involvement of any immune cells, instead getting its start with the fibroblasts.
Basically, people have been looking at the outside-in pathway, Seykora said. What we have here is more what we would call an inside-out mechanism.
Whatever the initial cause, the inflammation leads to dry, cracked skin, which in turn may allow more dust mites to penetrate. The end result, for far too many, is a cycle of misery.
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