Investigating the Causes of Chronic Itch: New Advances Could Bring Relief
Chronic itch, which occurs in many medical conditions and in response to certain drugs, affects millions of Americans, yet its causes are poorly understood. Now, investigators funded in part by the NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases have uncovered previously unknown pathways that trigger chronic itch, painting a clearer picture of the condition and suggesting novel therapeutic strategies.
Itch was once thought to be sensed through the body’s pain pathways, but research over the past few decades has revealed that it uses its own dedicated nerves, molecules and receptors. While itch is ultimately conveyed through nerves to the brain, the most well-understood itch pathway initiates with immune molecules called histamines. Histamines normally serve a protective immune function by helping combat invading pathogens, but they also trigger the itchiness caused by a mosquito bite or a bout of hives by acting on sensory nerves in the skin.
Antihistamines help relieve short-lived itching caused by allergies or insect bites, but they only partially alleviate the chronic itching in diseases like eczema or psoriasis. Part of the problem is that scientists don’t have a clear understanding of the pathways that cause the unrelenting itch in these conditions.
Chronic itch likely stems from many factors, and researchers are following different leads to find them. Three recent studies have examined the possible contributors and will aid the ongoing search for more effective treatments.
Nerve Cells: Itch First Responders
While much of the research on itch has centered on indirect immune triggers like histamines, Diana Bautista, Ph.D., a professor at the University of California, Berkeley, suspected that some molecules could directly act on nerve cells in the skin. Her team focused on a protein produced by damaged skin cells called thymic stromal lymphopoietin (TSLP), which had previously been linked to chronic itch associated with eczema, or atopic dermatitis.
In a bundle of sensory nerve cells, only a small number are sensitive to TSLP (left). By comparison, a larger fraction responds to capsaicin (right), the component of chili peppers that produces the burning sensation. Credit: Diana Bautista, Ph.D., University of California, Berkeley.
Earlier studies had shown that TSLP, when injected into the skin of laboratory mice, caused them to scratch. It was generally assumed that the itch occurred through activation of mast cells, a type of immune cell that produces histamines. But Dr. Bautista’s team discovered that TSLP brought about the scratching behavior even in mice lacking these cells, suggesting that another mechanism was at work.
Further experiments uncovered a molecular receptor for TSLP on certain skin nerve cells, and showed that the protein acts directly on these cells to transmit itch signals.
While TSLP is also thought to promote itch through immune molecules, Dr. Bautista’s work suggests that the nervous system itself could play a larger role than expected in directly promoting the sensation. If TSLP is the primary trigger, as Dr. Bautista suspects, then blocking the molecule’s activity could stop the inflammation and chronic itch that characterize eczema.
"Only a small minority of neurons in the skin respond to TSLP,” said Dr. Bautista. “If we could find a way to specifically target theses neurons without affecting other sensory pathways like pain and touch, we could have the beginnings of a new treatment for chronic itch that would not impact these other critically important functions."
Itching by Borrowing From Pain
Another study led by Zhou-Feng Chen, Ph.D., director of the Center for the Study of Itch at Washington University in St. Louis, also focuses on nerve cell involvement in chronic itch. His team was interested in a protein called BRAF, which is known to help convey pain signals from sensory nerves in the skin to the brain.
Activated BRAF (represented in red), when introduced into sensory nerve cells in mouse skin, triggers the itch sensation. Credit: Zhou-Feng Chen, Ph.D., Washington University in St. Louis.
To gain a better understanding of BRAF’s function, the researchers introduced a continually active version of the molecule into sensory neurons in mice. They expected the mice to show signs of pain, but to their surprise, instead the mice scratched incessantly.
Additional experiments revealed that the cells containing activated BRAF produced elevated levels of a key itch-inducing signaling protein called gastrin-releasing peptide (GRP).
Moreover, the team also noticed that the activated BRAF-containing cells triggered GRP production in many more neighboring, pain-sensing cells. Dr. Chen suspects that the recruitment of these pain-sensing neurons intensifies the itch sensation and could explain why chronic itch is so uncomfortable.
The researchers also showed that tamping down BRAF activity or GRP signaling reduced the scratching behavior in the mice, suggesting that blocking the BRAF pathway could be an effective strategy for developing novel anti-itch therapies.
"Using BRAF, we have created a mouse with chronic itch that appears similar to the incessant itching that people experience in diseases like eczema and allergic contact dermatitis," said Dr. Chen. "Scientists can now use this mouse model to further explore the biochemical mechanisms that underlie itch, and use it to test experimental drugs."
An unusual characteristic of people with eczema is the prevalence of Staphylococcus aureus bacteria on their skin—90 percent of patients harbor the microbe. Gabriel Núñez, M.D., a professor at the University of Michigan Health System, wondered what role, if any, the bacteria played in the disease.
To investigate the possibility that Staphylococcus aureus produces a protein that contributes to the skin inflammation and itching in people with eczema, Núñez’s team began by collecting all the proteins secreted by the bacterium. The researchers then bathed laboratory-grown mast cells in a cocktail of these proteins to see if the cells would release their itch-provoking histamines. They focused on mast cells because previous research had indicated that these cells played a key role in eczema.
The results clearly showed that Staphylococcus aureus stimulates mast cells—they quickly discharged their histamines in response to the bacterial protein mixture.
Next, they identified the specific bacterial protein found in Staphylococcus aureus responsible for the effect, a molecule called delta toxin. When they infected mice with normal Staphylococcus aureus, the mice’s skin became inflamed, but when they used a strain that had been engineered to lack delta toxin, their skin remained largely healthy. Applying delta toxin to the mice’s skin caused eczema-like symptoms, further implicating the protein in the disease.
Mast cells harbor dozens of histamine-laden granules (left) but when stimulated by delta toxin (right) the granules are expelled into the cell’s surroundings. Credit: Gabriel Núñez, M.D., University of Michigan Health System.
Delta toxin’s exact function is not known, but previous research suggests that it may kill competing bacteria in the skin.
"Staphylococcus aureus probably doesn’t make delta toxin to cause disease in people," said Dr. Núñez. "What we know about the protein suggests that the inflammation it causes in human skin could simply be collateral damage in a battle among microbes for a specific niche in the host’s body."
In future work, Dr. Núñez plans to search for ways to curb the effects of delta toxin, for example, by identifying its receptor on mast cells, then testing various approaches to blocking it. He also plans to examine eczema patients to see if delta toxin plays a similar role in people.
The research reported in this article was supported in part by NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases [grant numbers R01AR059385 (Bautista), R01AR056318 (Chen) and R01AR059688 (Núñez)].
Kirstie Saltsman, Ph.D
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The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Wilson SR, Thé L, Batia LM, Beattie K, Katibah GE, McClain SP, Pellegrino M, Estandian DM, Bautista DM. Cell. 2013 Oct 10;155(2):285-95. doi: 10.1016/j.cell.2013.08.057. Epub 2013 Oct 3. PMID: 24094650
Chronic itch development in sensory neurons requires BRAF signaling pathways. Zhao ZQ, Huo FQ, Jeffry J, Hampton L, Demehri S, Kim S, Liu XY, Barry DM, Wan L, Liu ZC, Li H, Turkoz A, Ma K, Cornelius LA, Kopan R, Battey JF Jr, Zhong J, Chen ZF. J Clin Invest. 2013 Oct 15. pii: 70528. doi: 10.1172/JCI70528. [Epub ahead of print] PMID: 24216512
Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. Nakamura Y, Oscherwitz J, Cease KB, Chan SM, Muñoz-Planillo R, Hasegawa M, Villaruz AE, Cheung GY, McGavin MJ, Travers JB, Otto M, Inohara N, Núñez G. Nature. 2013 Nov 21;503(7476):397-401. doi: 10.1038/nature12655. Epub 2013 Oct 30. PMID:24172897
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