Catastrophic skin itching caused by severe liver disease has been found to have surprising causes. The findings show the potential for new treatments for itching, showing that the outer layers of the skin are more than adiabatic.
Survey results displayed on April 2 GastroenterologyShows that keratinocyte cells on the surface of the skin function as principal investigators Wolfgang Liedtke, MDPhD, what they call “preneurons.”
“The skin cells themselves are sensuous under certain conditions, especially under the outermost layer of cells, keratinocytes,” said Liedtke, a professor of neurology at Duke University School of Medicine.
Collaborated with colleagues at Wake Forest University in Mexico, Poland, and Germany, this study of itching in liver disease revealed Liedtke’s understanding of cell surface calcium-permeable ion channels called TRPV4, discovered 20 years ago by Rockefeller. Is a continuation of the pursuit of. University.
TRPV4 channels play an important role in many tissues, including the sensation of pain. It was known to be present in skin cells, but no one knew why.
“The first idea was that it plays a role in skin stratification and skin barrier function,” Liedtke said. “But this current study has led us to the more stimulating areas of the skin that are actually exposed to the moonlight as sensory organs.” Upon receiving the chemical signal of itching, keratinocytes are next to the spine. It relays signals to the nerve endings in the skin, which belong to the nerve cells that sense itching in the posterior root ganglia.
“Dr. Liedtke and I have long been interested in the role of TRPV4 in the skin. Based on previous collaboration, we decided to focus on chronic itch,” said Duke’s Neurology. Associate professor and researcher.
Researchers have found that a liver disease called primary biliary cholangitis (PBC) has an excess of phospholipidyl or fat lysophosphatidylcholine (LPC) that circulates in the bloodstream. They then showed that LPCs injected into the skin of mice and monkeys cause itching.
Next, they wanted to understand how this lipid could lead to an aggressive itching sensation. “If itching occurs in PBC, it is so debilitating that the patient may need a new liver, which is how bad it can be,” Liedtke said. Importantly, the skin is not chronically inflamed with PBC, so in the absence of chronic skin inflammation there is debilitating itching.
Researchers have found that when LPCs reach the skin, lipids can bind directly to TRPV4. When bound, it directly activates the ion channel and opens the gate for calcium ions. Calcium ions are a universal switching mechanism for many cellular processes.
But in this case, the signal does something amazing. Researchers tracked an intracellular signaling cascade in which one molecule is passed to another, resulting in the formation of small bubbles called vesicles on the surface of skin cells. Vesicles are designed to germinate cells and carry away everything inside them.
In this case, the bubbles contained something amazing. It was a microRNA and functioned as a signaling molecule. “This is strange because microRNAs are usually known to be gene regulators,” Liedtke said.
It turns out that this particular bit of microRNA is itself a signal that causes itching.
When identified as microRNAmiR-146a, researchers found that the molecule was injected alone into mice and monkeys, causing itching immediately, rather than hours later, as it would when regulating genes. Did.
“Future research will address which specific itch sensory neurons respond to miR-146a and their detailed mechanisms beyond the TRPV1-dependent signaling we have discovered,” Chen said. I will.
With the help of German and Polish liver specialists who have blood draws and itch data for PBC patients, researchers found that blood levels of microRNA-146a correspond to the severity of itch as well as LPC levels. I found.
Knowing all parts of signal transduction from excess phospholipids, LPCs to intolerable itching gives scientists a new way to look for advanced liver disease markers, Rietke said.
And it presents a new way to treat itching by either desensitizing the TRPV4 channels in the skin with topical treatments, attacking specific microRNAs that cause itching, or target depletion of LPCs.
The sensation of itching is due to the skin cells themselves after signaling from excess lipids-ScienceDaily
https://www.sciencedaily.com/releases/2021/04/210406182904.htm The sensation of itching is due to the skin cells themselves after signaling from excess lipids-ScienceDaily