Mechanism of Horrible Itching of Liver Disease Identified in Superficial Skin Cells Interview with:

Wolfgang Liedtke, M.D., Ph.D. Chair of Neurology Global Development Scientific Council Regeneron Pharmaceuticals Tarrytown NY 10591

Dr. Liedtke

Wolfgang Liedtke, M.D., Ph.D.
Professor (tenured) of Neurology, Anesthesiology and Neurobiology
Attending Physician, Duke Neurology Clinics for Headache, Head-Pain and Trigeminal Sensory Disorders
Attending Physician, Duke Clinics for Innovative Pain Therapy at Brier Creek (Dept of Anesthesiology)
Duke University School of Medicine, Center for Translational Neuroscience
Durham NC 27710
Since April 2021
Chair of Neurology
Global Development Scientific Council
Regeneron Pharmaceuticals
Tarrytown NY 10591 What is the background for this study?

Response: There are systemic diseases that are characterized by intense itching, yet without inflammation of the skin and not associated with allergic inflammation. For example and importantly, liver disease with non-functional secretion of bile (cholestatic liver disease, most common primary biliary cholangitis, an autoimmune disease), but also chronic end-stage renal disease (also certain lymphomas and pruritic psoriasis where the itch is whole-body, not only restricted to diseased skin).

We thought that these diseases might be great starting points to better understand itch because there is no inflamed skin and no allergies. Thus, there must be some systemic factor that causes itch, and we were intent on discovering such factors, and with them, molecular mechanisms how they cause itch.

For cholestatic liver disease, one of the best candidates to fit this profile has been lysophosphatidic acid (LPA), since the pioneering discoveries of Andreas Kremer, one of our co-authors.

My research laboratory at Duke has been rooted in my discovery of TRPV4 ion channels 20 years ago, out of the Friedman Lab at The Rockefeller University in NYC. Over the years, with my colleague Yong Chen out of my lab, now leading his own independent research operation, we focused on the role of TRPV4 ion channels in skin. 5 years ago Yong and I published a paper that provided some evidence for TRPV4 in skin perhaps playing a role in itch.

Working with phospholipids, we made the serendipitous discovery that lysophosphatidyl choline (LPC) is a more potent itch-inducing lipid molecule than LPA. Of note, LPC is the metabolic precursor of LPA. We then found that LPA does not depend on TRPV4 to elicit itch. The more robust itch evoked by LPC was significantly reduced when we knocked down TRPV4 in skin keratinocytes. Itch was NOT affected when TRPV4 was deleted from sensory nerve cells that innervate the skin.

In terms of background, my long-term goal has been to elucidate how innervating peripheral nerve cell and innervated organ, such as skin, talk to one another so that the sensation that is felt is regulated or modulated, e.g how can skin influence itch or pain, how can joint cells influence pain.

That became the exciting bedrock of our study, and we took it from there, 5 years of hard work with collaborations spanning the globe, and a final stretch of exhausting work during the pandemic. What are the main findings?

  1. LPC is a powerful itch-inducing molecule (pruritogen), in mice and in monkeys.
  2. LPC is significantly elevated in the blood of patients with PBC who itch vs those who do not. Level of itch correlates with level of LPC, when examining a German and a Polish cohort of PBC patients.
  3. The mechanism how LPC causes itch is summarized in our Summary Figure. LPC binds to TRPV4 (calcium permeable ion channel), to a part of the molecule right inside the cell, right next to the plasma membrane and next to the subdomain where calcium rushes through TRPV4. This binding activates TRPV4 ion channels, the gate opens and calcium rushes into the cell. Calcium rushing through TRPV4 into skin covering cells, skin keratinocytes, switches these cells into itch-generator cells. The signaling cascade inside the keratinocyte is: LPC==>TRPV4==> calcium influx==> activation of MAP-kinase signaling including MEK/ERK phosphorylation ==> extrusion of vesicles out of the keratinocyte, vesicular exocytosis, depending on the Rab5a/Rab27a proteins, thus possibly a process referred to as exosomal extrusion ==> vesicles (exosomes) contain a small, regulatory RNA molecule, microRNA-146a ==> miR-146a activates itch-inducing sensory neurons that innervate the skin that express the TRPV1 capsaicin receptor ion channel. This activation functions like a peptide or hormone activating a cell surface hormone receptor, NOT by interfering with gene regulation (that aspect radically breaks with existing molecular biology dogma) ==> TRPV1+ pruriceptors evoke itch via previously described neural circuits. Is this a different cutaneous system than through Langerhans cells?

Response: YES. This is a crosstalk between skin epithelial cells, keratinocytes, the vastly most abundant epithelial cell in the human and vertebrate skin, and skin-innervating sensory neurons located in the dorsal root ganglion (DRG) and trigeminal ganglion (TG; for head-face).

Langerhans cells are specialized immune-players, and in terms of abundance vs keratinocytes they are super-rare. Does it apply to other forms of itch?

Response: This remains to be seen, LPC is also elevated in chronic renal disease and in psoriasis lesions.

With our findings, all of these forms of chronic itch and other forms of chronic itch can be interrogated whether LPC molecules, miR-146a are elevated systemically and in sites of itch (skin areas, also genital areas, conjunctivae of the eyes). What should readers take away from your report?

1) the skin can function as a sensory organ through its epithelial cells, keratinocytes, which can assume a quasi-neural function, telling itch neurons what to do by directly signaling to them cell-to-cell.

2) this is NEW and has not been understood by now. Keratinocytes talk to sensory neurons by vesicle release and the equivalent to the neurotransmitter is a micro-RNA (miR146a) which functions like a transmitter or like a hormone (not like a gene-regulatory classic microRNA)

3) this is an intriguing example of how sensory molecules, TRP ion channels, can work together in a biological process (or better, a patho-biological process – cholestatic itch): TRPV4 on keratinocytes ==> TRPV1 on sensory neurons that transduce and transmit itch.

4) we now understand better a systemic disease that can be complicated by a horrible sensory process, chronic refractory itching, namely we have elucidated the molecular logic of cholestatic itch better, reaching higher resolution

5) emerging targets to fight this disease are: TRPV4 on keratinocytes, TRPV1 on sensory neurons, MEK/ERK signal transduction and vesicular exocytosis of keratinocytes, microRNA-146a as the secreted molecule from keratinocytes that tells itch neurons what to do, LPC as powerful pruritogen in cholestatic itch, possibly in other systemic pruritic diseases

6) LPC, miR-146a, TRPV4 expression and function of skin keratinocytes: all of these can be used as biomarkers of cholestatic itch

7) since we have elucidated how LPC activates TRPV4, including a high-likelihood binding site, new compounds can be rationally developed that bind to TRPV4 AT THIS SITE and activate or inactivate the channel. This could be transformative progress over existing approaches of TRPV4 activators and inhibitors that already exist. What recommendations do you have for future research as a result of this work?

This is a powerful new chapter in this arena. Follow up can be:

  • — more precise mechanisms how miR-146a activates TRPV1+ pruriceptor neurons
  • — identify compounds that bind to TRPV4 in the identified LPC binding site
  • — confirm via structural studies (cryoEM of the channel) that LPC does bind there ==> how does the channel look once it is bound ?
  • — in patients, conduct studies about LPC and miR146a as biomarkers
  • — translational studies with focus on the above target
  • — extend on the vesicular exocytosis mechanism of miR-146 from skin keratinocytes
  • — do keratinocytes from different patient populations behave differently ?


Epithelia-sensory neuron crosstalk underlies cholestatic itch induced by lysophosphatidylcholine

Chen, Yong et al. Gastroenterology, Volume 0, Issue 0


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Apr 6, 2021 @ 12:38 am

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