The maddening itch of liver disease comes from an amazing source

A devastating itchy skin caused by severe liver disease turns out to have an amazing cause. His discovery points to possible new therapies for itching and shows that the outer layer of the skin is much more than isolation.

The discovery, which appears on April 2 in Gastroenterology, indicates that keratinocyte cells on the skin’s surface are acting as what researcher Wolfgang Liedtke, MD Ph.D., calls ‘pre-neurons’.

“The skin cells themselves are sensory under certain conditions, specifically the outermost layer of the cells, keratinocytes,” said Liedtke, who is a professor of neurology at the Duke School of Medicine.

This itchy liver disease study, done with colleagues in Mexico, Poland, Germany and Wake Forest University, is a continuation of Liedtke’s quest to understand a calcium permeable ion channel on the cell surface called TRPV4, which he discovered 20 years ago. years at Rockefeller University.

The TRPV4 channel plays a crucial role in many tissues, including the sensation of pain. It was known to exist in skin cells, but no one knew why.

“The initial ideas were that it plays a role in the way the skin is formed and in the skin’s barrier function,” said Liedtke. “But this current research is taking us to more exciting territory of the skin, which actually functions as a sensory organ.” As soon as a chemical itch signal is received, keratinocytes transmit the signal to the nerve endings of the skin that belong to itch sensitive nerve cells in the dorsal root ganglion near the spine.

“Dr. Liedtke and I had a longstanding interest in the role of TRPV4 in the skin. Based on our previous collaborations, we decided to focus on chronic itching,” said Yong Chen, assistant professor of neurology at Duke, the study’s first author. .

The researchers found that in a liver disease called primary biliary cholangitis (PBC), patients are left with an excess of lysophosphatidylcholine (LPC), a phosphorylated lipid, or fat, circulating in the bloodstream. They then demonstrated that LPC, injected into the skin of mice and monkeys, causes itching.

Next, they wanted to understand how this lipid could lead to the feeling of aggressive itching. “If the itch appears in the PBC, it is so debilitating that patients may need a new liver. That’s how bad it can get,” said Liedtke. It is important to note that the skin is not chronically inflamed in PBC, which means that there is debilitating itching in the absence of chronic skin inflammation.

The researchers found that when LPC reaches the skin, the lipid can bind directly to TRPV4. Once turned on, it directly activates the ion channel to open the door for calcium ions, which are a universal exchange mechanism for many cellular processes.

But in this case, the signal does something surprising. The researchers followed a signaling cascade inside the cell in which one molecule passes to another, resulting in the formation of a small bubble back on the surface of the skin cell called the vesicle. Vesicles are designed to detach from cells and carry whatever is inside them.

In this case, the bubbles contained something surprising: micro-RNA, and it functioned as a signaling molecule. “This is crazy, because microRNAs are commonly known as gene regulators.” Liedtke said.

It turns out that this particular bit of microRNA is the very signal that causes the itch.

After identifying it as microRNA miR-146a, the researchers injected the molecule alone into mice and monkeys and found that it caused itching immediately, not hours later, as it would if it were regulating genes.

“Future research will address which specific itchy sensory neurons respond to miR-146a, in addition to the TRPV1-dependent signaling we found, also its mechanism in depth,” said Chen.

With the help of German and Polish liver specialists who have blood samples and itch data in patients with PBC, the researchers found that the levels of microRNA-146a in the blood corresponded to the severity of the itch, as well as the levels of LPC.

Knowing all the parts of the signaling that leads from excess phospho-lipid, LPC, to intolerable itching, gives scientists a new way to look for advanced markers of liver disease, said Liedtke.

And it points to new ways to treat itching, possibly by desensitizing the TRPV4 channels in the skin with a topical treatment, attacking the specific microRNAs that drive itching or targeted depletion of LPC.