The study in mice paves the way for future research into the skin–nerve–brain communication errors that occur in disorders such as dermatitis and psoriasis and could inform the development of new topical treatments for these conditions.
“Our sense of touch (both touching and being touched) impacts our daily life, activities and communication with other people and animals. For such a widely occurring phenomenon, surprisingly little is known about the mechanism underlying how touch signals are conveyed to the brain,” says lead author Francie Moehring, senior neuroscience graduate student in the laboratory of Cheryl Stucky, Professor of Cell Biology, Neurobiology & Anatomy, and Director of the Neuroscience Doctoral Program, at the Medical College of Wisconsin, Milwaukee, US
“Most people think that when they touch something or someone, nerve cells alone are responsible for sending information to the brain, but recent research has shown that our skin also plays a significant role. Since the skin covers nearly our entire body, it could have an important signaling role from our head to toes. We wanted to find out exactly how the skin communicates our contact with both harmless and painful touch stimuli to our sensory neurons.”
The first point of the body’s contact with physical objects is the epidermis, the outermost layer of skin that is largely made up of cells called keratinocytes. After determining that these skin cells have a functional role in sensing touch, the researchers used a light stimulation technique (optogenetics) to inhibit the cells in mice. They found the animals’ sensitivity to harmless and painful touch was reduced when both touch and light inhibition were applied to their hindpaw.
Next, the team sought to determine the molecules that mediate communication between keratinocytes and sensory neurons. In particular, they investigated a chemical called adenosine triphosphate (ATP) in the mice and found that increasing the touch stimulation to their hindpaw skin resulted in increased ATP release and that keratinocytes were the specific source of ATP.
“The next step was to find out which sensory nerve receptor responds to the ATP released from the keratinocytes during touch stimulation,” says senior author Cheryl Stucky. The team inhibited a protein receptor called P2X4 in the animals’ sensory neurons and saw that it decreased their sensitivity to touch stimulation. Similar tests on P2X2 and P2X3, relatives of P2X4, had no such effect, suggesting that the touch-induced release of ATP from keratinocytes most likely acts through P2X4 receptors alone.
“Altogether, our results reveal that skin keratinocytes are indispensable for both harmless and painful touch sensation,” Moehring explains. “These keratinocyte cells in the top layer of skin communicate with sensory neurons inside the skin via the release of ATP, which then activates P2X4 receptors on sensory nerve terminals that signal touch perception to the brain.”
Stucky concludes: “Many skin disorders are characterised by altered skin function and signaling, and share pain and itch as common debilitating symptoms. Building on our work to understand how the skin can change its normal communication with nerve cells under these disease and injury conditions could lead to improved and non-invasive topical treatments that specifically target the site of pain in the skin.”
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