Two new UC Davis Health studies explore how differences in skin composition contribute to skin conditions such as psoriasis and atopic dermatitis.
“The composition of the skin is not uniform throughout the body,” said Emanual Maverakis, professor of dermatology and molecular medical microbiology at UC Davis and senior author of both studies. “Different skin characteristics in different body parts may influence the skin’s susceptibility to certain diseases.”
Skin diseases affect approximately 84.5 million Americans. Aging, trauma, environmental and genetic factors can lead to a variety of skin conditions.
Body site determines skin structure and function and disease susceptibility
The skin is the largest organ of the human body. Its average size is about 20 square feet – that’s the size of a 4 foot by 5 foot 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 meet the environmental challenges unique to each area of the body. For example, facial skin needs to be thin and elastic to accommodate facial expressions. The skin covering the heel must be thick and hard to withstand the force and protect it from the objects we step on.
Skin composition depends on a variety of factors, including the structure of the skin barrier, cell types and the genes they express.
Until recently, little was known about the cellular and molecular processes underlying these differences. In the first study, the researchers showed the mechanism responsible for these changes in skin structure.
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 keratinocytes differ in different body parts. They also used targeted molecular profiling to characterize the molecules that form the “mortar” between keratinocytes. They then examined how these differences in gene expression matched the compositional differences in lipid and protein structures in body parts. These experiments explain why skin on different body parts looks so different.
Differences in the composition of skin lipids and proteins in different body parts may also explain why different skin diseases are found in different body parts. In describing the specific lipid changes associated with various skin diseases, the researchers found that the lipids that adhered to the tape attached to the skin were sufficient to diagnose patients with a specific skin disease.
“These findings will lead to non-diagnostic tests for common skin conditions,” said co-lead author Alexander Merleev, project scientist.
“These differences are also relevant to the future design of skin care products,” said study co-lead author Stephanie Le, a dermatology resident. “They show how skin care products should be specially formulated to match the specific body part they will be applied to.”
Psoriasis and the immune system
In the second study, the team looked at how skin cells interact with the immune system.
Previously, keratinocytes were known to secrete substances that increase and decrease inflammation. Using single-cell sequencing to analyze each keratinocyte individually, the researchers observed that these immunomodulatory molecules were expressed in certain layers of the epidermis.
Keratinocytes in the lowest 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, waiting patiently against any pathogenic microorganisms or parasites that might breach the skin’s physical barrier. In contrast, they found that keratinocytes in the outer layer of the epidermis secrete pro-inflammatory molecules, particularly IL-36.
IL-36 is a major mediator of a subtype of psoriasis, an inflammatory skin disease. The team found that the amount of IL-36 in the skin is regulated by another molecule called PCSK9, and that individuals with mutations in the PCSK9 gene are more likely to develop psoriasis.
“We found that different layers of the skin secrete different immune mediators, which is an example of how the skin is highly specialized to interact with the immune system. When the molecules secreted by the skin are unbalanced, some people develop skin diseases, such as psoriasis. different layers of the skin,” said study co-lead author Antonio Jixu, a researcher at the University of California, Davis.
Both studies were published in JCI Insights.