Why are some parts of the body more prone to skin diseases than others?
Two new studies from UC Davis Health have explored how differences in skin composition can lead to dermatological conditions, such as psoriasis and atopic dermatitis.
The skin does not have a uniform composition throughout the body. Different characteristics of the skin at different locations on the body can affect the skin’s susceptibility to certain diseases.”
Emanual Maverakis, professor of dermatology, molecular medical microbiology at UC Davis and lead author
Skin diseases affect approximately 84.5 million Americans. Aging, trauma, and environmental and genetic factors can lead to a wide range of skin conditions.
Body site determines skin structure and function and susceptibility to disease
The skin is the body’s largest organ. It averages about 20 square feet – that’s the size of a 4′ by 5′ room! Its outermost layer (the epidermis) has a lipid matrix composed of free fatty acids, cholesterol and ceramides (a family of waxy lipid molecules).
This layer must respond to the environmental issues specific to each area of the body. For example, facial skin should be thin and supple to accommodate facial expressions. The skin that covers the heel of the foot must be thick and rigid to resist the force and protect it from the objects we walk on.
The composition of the skin depends on several factors, including the structure of the skin barrier, the types of cells and the genes they express.
Until recently, little was known about the cellular and molecular processes behind these differences. In the first study, the researchers showed the mechanisms that lead to these structural changes in the skin.
The epidermis has a “bricks and mortar” structure: molecules like ceramides, cholesterol and fatty acids make up the “mortar” and cells called keratinocytes are the “bricks”.
The researchers used single-cell sequencing to characterize how keratinocytes differ at different sites in the body. They also used targeted molecular profiling to characterize the molecules that form the “mortar” between keratinocytes. They then examined how these gene expression differences corresponded to compositional differences in lipid and protein structures across body sites. These experiments explained why skin looks so different at different sites on the body.
Differences in the composition of skin lipids and proteins at different sites of the body may also explain why different skin diseases are found at different sites of the body. By characterizing the specific lipid alterations associated with various skin diseases, researchers found that lipids stuck to a piece of adhesive tape applied to the skin were sufficient to diagnose a patient with a particular skin disease.
“These findings will lead to non-diagnostic tests for common dermatological diseases,” said co-lead author, project scientist Alexander Merleev.
“These differences are also relevant for the future design of skin care products,” said Stephanie Le, dermatology resident and co-lead author of the study. “They demonstrate how skincare products need to be specifically formulated to match the particular body site they will be applied to.”
Psoriasis and the immune system
In the second study, the research team investigated how skin cells interact with the immune system.
Previously, it was known that keratinocytes could secrete substances that both increase and decrease inflammation. By using single-cell sequencing to analyze each keratinocyte individually, the researchers observed that these immunomodulatory molecules were expressed in certain layers of the epidermis.
The keratinocytes of the lowest layer of the epidermis secrete immune-attracting and anti-inflammatory molecules. It involves attracting immune cells to the skin and parking them in place to wait patiently to fight off any pathogenic microbes or parasites that might cross the skin’s physical barrier. On the other hand, they found that the keratinocytes of the outer layer of the epidermis secrete pro-inflammatory molecules, in particular IL-36.
IL-36 is a primary mediator of a subtype of psoriasis, an inflammatory skin disease. The team found that the amount of IL-36 in the skin was regulated by another molecule called PCSK9 and that individuals with variations in their PCSK9 gene were predisposed to developing psoriasis.
“Our discovery that different layers of the skin secrete different immune mediators is an example of how the skin is highly specialized to interact with the immune system. Some people develop skin diseases, such as psoriasis, when there is an imbalance in the molecules secreted by the different layers of the skin.” said Antonio Ji-Xu, a researcher at UC Davis, co-lead author of the study.
Both studies were published in JCI Overview.
University of California – Davis Health
Merleev, AA, et al. (2022) Biogeographic and disease-specific alterations in epidermal lipid composition and single-cell analysis of acral keratinocytes. JCI Overview. doi.org/10.1172/jci.insight.159762.