The itching sensation arises in the skin cells themselves, after an indication of an excess of sebum
Durham, North Carolina – The devastating itchy skin of acute liver disease has been shown to have a surprising cause. His discovery points to potential new treatments for itching, and shows that the outermost layer of the skin is much more than just an insulating material.
The result, which appears on April 2 in Digestive system diseases, Indicates that the cells of the keratinocytes on the surface of the skin function as lead researcher Wolfgang Liedtke, MD, calls them “pre-neurons.”
“Skin cells themselves are sensitive under certain conditions, specifically the outer layer of cells, the keratinocytes,” said Lidtec, professor of neuroscience at Duke University School of Medicine.
This study of liver disease pruritus, conducted with colleagues in Mexico, Poland, Germany and Wake Forest University, is a continuation of Liedtke’s quest to understand a cell-surface calcium-permeable ion channel called TRPV4, which he discovered 20 years ago in Rockefeller. University.
The TRPV4 channel plays an important role in many tissues, including the perception of pain. It was known to be present in skin cells, but no one knew the cause.
“The initial ideas were that it plays a role in how layers of skin are formed, and in the function of the skin barrier,” Lydec said. “But this current research is causing us to reach a more exciting area of skin that is actually a sensory organ.” Once they receive a chemical signal for itching, the keratinocytes transmit the signal to the nerve endings in the skin that belong to the itch-sensing neurons in the dorsal root node next to the spine.
Dr. Yong Chen, associate professor of neuroscience at Duke University and first author of the study, said, “I and you have had a long-term interest in the role of TRPV4 in the skin, based on our previous collaboration, we decided to focus on chronic pruritus.”
Researchers have found that in a liver disease called primary cholangitis (PBC), patients are left with an excess of lysophosphatidylcholine (LPC) which is a phospholipid, or lipid, circulating in the bloodstream. Then they demonstrated that injecting LPC into the skin of mice and monkeys provokes itching.
Then they wanted to understand how this sebum can cause intense itching. “If itching appears in PBC, it is so debilitating that patients may need a new liver. That’s how bad it can get,” he told Lydec. Most importantly, the skin is not chronically inflamed in PBC, which means that There is a debilitating itch in the absence of chronic dermatitis.
The researchers found that when LPC reaches the skin, the lipid can bind directly to TRPV4. Once bound, it directly activates the ion channel to open the gate of calcium ions, which is a universal switching mechanism for many cellular processes.
But in this case, the signal does something surprising. The researchers followed a chain of signals inside the cell as one molecule traveled to another, resulting in the formation of a small bubble on the surface of the skin cell called a vesicle. Vesicles are designed to sprout cells and carry everything inside away.
In this case, the bubbles contained something surprising: micro-RNA, acting as a signaling molecule. “This is crazy, because microRNAs are usually known to be epigenetic regulators.” Liedtke said.
It turns out that this particular part of the microRNA is itself the itch-triggering signal.
Once identified as microRNA miR-146a, the researchers injected the molecule alone into mice and monkeys and found that it immediately caused itching, not hours later, as if it was regulating genes.
“Future research will look at which specific sensory neurons respond to miR-146a, as well as the TRPV1 dependent signal that we found, as well as its in-depth mechanism,” Chen said.
With the help of German and Polish hepatologists who had blood pooling and pruritus data on PBC patients, the researchers discovered that the blood levels of microRNA-146a matched the severity of the itch, as well as the LPC levels.
Lydec said that knowing all the parts of the signal that lead from excess lipophosphate, LPC, to unbearable itch gives scientists a new way to look for advanced markers of liver disease.
It suggests new approaches to treating pruritus, either by desensitizing TRPV4 channels in the skin with a topical treatment, attacking specific microRNAs that cause itching, or targeted depletion of LPC.
This research was supported by the US National Institutes of Health (DE018549, K12DE022793, R01DE027454), the Michael Ross Hafner Foundation (Charlotte, NC), and the General Directorate of Academic Personnel Affairs (DGAPA) – Technology Research and Innovation Projects Support (PAPT) Program (IN200720) ; National Council of Science and Technology (CONACyT) (A1-S-8760) and the Secretariat of Education, Science, Technology and Innovation of the Government of Mexico City (SECTEI / 208/2019).
Quote: “Sensory neuron interference underlies biliary pruritus induced by lysophosphatidylcholine”, Yong Chen, Zi Long Wang, Michelle Yu, Qiao Guan Zhang, Anna E Lopez Romero, Hui Bing Ding, Xin Zhang, Qian Zheng, Sara El Morales Lazaro Carlin Moore, Ying I Jin, Huang Hee Yang, Johannes Morstein, Andre Burtsov, Marcin Krausek, Frank Lammert, Manal Abdel Malik, Anna May Dell, Piotr Milkwitch, Andreas E. Kremer, Jennifer Way. Chang, Andrea Nuckley, Tony E. Reeves, Mi Chuan Kuo, Ro Rongji, Tamara Rosenbaum, and Wolfgang Lidtke. Digestive system diseasesApril 2, 2021.
DOI: 0.1053 / j.gastro.2021.03.049