Two new UC Davis Health studies examined how differences in skin composition can lead to dermatological conditions, such as psoriasis and atopic dermatitis.
“Skin does not have a uniform composition throughout the body,” said Emanual Maverakis, professor of dermatology, molecular medical microbiology at UC Davis and senior author of both studies. “Different skin features in different body locations can influence the skin’s susceptibility to certain diseases.”
Skin diseases affect approximately 84.5 million Americans. Aging, trauma, and environmental and genetic factors can lead to a wide variety of skin conditions.
Body location determines the structure and function of the skin and its susceptibility to disease
The skin is the largest organ in the body. It averages about 20 square feet – that’s the size of a 4′ by 5′ room! The outer layer (epidermis) has a lipid matrix made up of free fatty acids, cholesterol, and ceramides (a family of waxy lipid molecules).
This layer must meet the environmental challenges specific to each part of the body. For example, the skin of the face must be thin and flexible to allow for facial expressions. The skin covering the heel of the foot must be thick and stiff to withstand force and protect against objects we step on.
The composition of the skin depends on several factors, including the structure of the skin barrier, the cell types and the genes they express.
Until recently, little was known about the cellular and molecular processes behind these differences. In the first study, researchers demonstrated the mechanisms that lead to these structural changes in the skin.
The epidermis has a “brick and mortar” structure: molecules such as 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 the keratinocytes differ in different body locations. They also used targeted molecular profiling to characterize the molecules that make up the “mortar” between the keratinocytes. They then examined how these differences in gene expression matched the compositional differences in the lipid and protein structures at body sites. These experiments explained why the skin looks so different in different parts of the body.
The differences in the composition of the skin’s lipids and proteins at different body locations may also explain why different skin diseases are found in different body locations. In characterizing the specific lipid changes associated with various skin diseases, the researchers found that lipids taped to the skin on a piece of tape were enough to diagnose a patient with a particular skin disease.
“These discoveries will lead to non-diagnostic testing for common dermatological conditions,” said co-lead author, project scientist Alexander Merleev.
“These differences are also relevant to the future design of skin care products,” said Stephanie Le, a dermatology resident and co-lead author of the study. “They show how to specifically formulate skin care products to suit the specific body site they will be applied to.”
Psoriasis and the immune system
In the second study, the research team studied how skin cells interact with the immune system.
It was previously known that keratinocytes can secrete substances that both increase and decrease inflammation. Using single-cell sequencing to analyze each keratinocyte individually, the researchers noted that these immune-modulating molecules were expressed in certain layers of the epidermis.
Keratinocytes in the lower layer of the epidermis secrete immune attracting and immune anti-inflammatory molecules. This is to attract immune cells to the skin and park them in place to wait patiently to fight off any pathogenic microbe or parasite that could break through the skin’s physical barrier. In contrast, they found that the keratinocytes in the outer layer of the epidermis secrete pro-inflammatory molecules, especially IL-36.
IL-36 is an important 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 skin secrete different immune mediators is an example of how the skin is highly specialized in interacting 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 skin.” the skin.” said UC Davis researcher Antonio Ji-Xu, co-lead author of the study.
Both studies were published in JCI Insight.