An investigation into the causes of severe pruritus associated with liver disease has revealed that under some circumstances, keratinocytes can function as sensory cells. The research team say this finding could lead to new treatments for itch.
In a press release, the study’s lead researcher Dr. Wolfgang Liedtke, said the keratinocytes are acting as ‘pre-neurons.’
Dr. Liedtke is a professor of neurology at Duke School of Medicine in Durham, N.C.
This study builds on earlier research by Dr. Liedtke regarding the calcium-permeable ion channel on the cell surface known as TRPV4. According to the release, this channel plays a crucial role in many tissues, including involvement in the sensation of pain. While TRPV4 was known to exist in skin cells, its function there was not understood.
The paper was published online ahead of print in Gastroenterology (April 2, 2021).
“The initial ideas were that it plays a role in how the skin is layered, and in skin barrier function,” Dr. Liedtke said. “But this current research is getting us into a more exciting territory of the skin actually moonlighting as a sensory organ.”
He said that once a certain chemical signal of itching is received, keratinocytes relay the signal to nerve endings in the skin that belong to itch-sensing nerve cells in the dorsal root ganglion next to the spine.
In this study, the researchers found that in the liver disease primary biliary cholangitis (PBC), patients are left with a surplus of the lipid lysophosphatidylcholine (LPC) circulating in the bloodstream. Tests in animal models then demonstrated that injecting LPC into the skin induced pruritus.
The next goal was to determine how LPC then led to the aggressive itching sensation experienced by people with PBC.
“If the itch comes up in PBC, it’s so debilitating that the patients might need a new liver. That’s how bad it can get,” Dr. Liedtke said.
One consideration in their research is that in PBC, the pruritus is not due to chronic inflammation.
The researchers found that when LPC reaches the skin, the lipid was able to bind directly to TRPV4. Once bound, it directly activated the ion channel. This, in turn, set off a signalling cascade within the cell, which resulted in the formation of extra-cellular vesicles containing micro-RNA. These micro-RNA proteins then acted as signalling molecules.
“This is crazy, because microRNAs are normally known to be gene regulators.” Dr. Liedtke said.
When the team isolated the specific micro-RNA, miR-146a, and tested in their animal models, it immediately induced itching, instead of causing it hours later as would be expected if miR-146a was regulating genes.
“Future research will address which specific itch sensory neurons respond to miR-146a, beyond the TRPV1-dependent signalling that we have found, also its in-depth mechanism,” said the paper’s first author, Yong Chen, PhD, in the release. Dr. Chen is an assistant professor of neurology at Duke University in Durham, N.C.
Examining blood samples and pruritus data on patients with PBC showed that blood levels of microRNA-146a corresponded to itch severity, as did the LPC levels.
Knowing all the parts of the signalling that leads from excess LPC to intolerable itching gives scientists a new way to look for advanced liver disease markers, Dr. Liedtke said.
As well, he said the findings point to new avenues for treating the pruritus, either by possibly desensitizing the TRPV4 channels in the skin with a topical treatment, attacking the specific microRNAs that drive the itch, or targeted depletion of LPC.