Tracing the Pathway From Skin Irritation to Itching
Tuesday, June 11, 2019
Building on findings published in 2013, IRP researchers recently identified the series of steps by which immune system cells in the skin called mast cells relay itch-related information to the brain.
For most people, the arrival of spring time means more time spent outdoors — and greater exposure to nuisances like biting insects and poison ivy that make us itch. New IRP research has revealed a detailed picture of how a particular type of cell causes itching, findings that may ultimately help researchers develop treatments for disorders that cause severe and long-lasting itch.1
In most cases, itching is temporary and no big deal, but for sufferers of skin ailments like psoriasis or eczema, it can significantly impact quality of life. Multiple cell types are known to trigger itching, including immune cells called mast cells, which release the itch-inducing chemical histamine during an allergic reaction. However, allergy treatments that block the action of histamine sometimes fail to relieve itching, suggesting that other chemicals produced in the body play important roles in itch.
Itch also relies on cells in the nervous system that relay sensory information from the skin to the brain. In 2013, researchers led by IRP senior investigator Mark Hoon, Ph.D., discovered that neurons that communicate with other cells using a chemical called natriuretic polypeptide b (Nppb) play a key role in this process.2 Nevertheless, it remained unclear how the body spurs Nppb neurons to send out itch-related signals.
“We figured that these cells must be responding to specific compounds that occur naturally in the body, but we didn’t know what they were,” says Dr. Hoon, the new study’s senior author.
To answer that question, Dr. Hoon’s research group teamed up with IRP Stadtman Investigator Alex Chesler, Ph.D. Their collaboration revealed that when mast cells are activated, they release three chemicals — LCT4, serotonin, and S1p — that stimulate Nppb neurons by binding to receptors on the neurons. Injecting mice with synthetic substances that activate only the specific variety of LCT4, serotonin, and S1p receptors found on Nppb neurons caused mice to start scratching at the injection site, even when the mice had no mast cells. On the other hand, mice that lacked Nppb sensory neurons scratched much less when exposed to those chemicals. Moreover, mice lacking only the specific S1p receptor found on Nppb neurons scratched very little when exposed to a synthetic chemical that binds only to that receptor, but they responded normally to a variety of other sensory information and itch-inducing chemicals.
The researchers also investigated how Nppb neurons activated by chemicals released from mast cells relay itch-related information to the brain, focusing on a spinal cord system identified in Dr. Hoon’s 2013 study. That system sends signals using a chemical called gastrin-releasing peptide (GRP). When the IRP scientists disrupted GRP-based communication along the spinal cords of mice, the animals scratched much less in response to the three synthetic substances that activate LCT4, serotonin, and S1p receptors on Nppb neurons. Meanwhile, the animals’ responses to stimulation unrelated to itch were unaffected, confirming that this pathway is specifically involved in itch.
“It’s a really nice study that traces this pathway from stimulus all the way to the spinal cord,” explains Dr. Chesler. “You can follow the logic all the way through from the outside of the body to the genesis of this scratching behavior.”
Researchers now need to determine how this system differs in humans compared to mice, as well as how it behaves differently in people with relentless, long-term itching. Nevertheless, now that scientists know all the steps by which itch-related signals from mast cells travel to the brain, they can begin looking into ways to disrupt that pathway when it behaves abnormally.
“We’re no longer wandering around in the dark not knowing how itch is generated,” Dr. Hoon says. “That is why basic research like this is important: ideas that are coming from basic research lead to clinical trials and new ideas about how to treat disease.”
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 Nppb Neurons Are Sensors of Mast Cell-Induced Itch. Solinski HJ, Kriegbaum MC, Tseng PY, Earnest TW, Gu X, Barik A, Chesler AT, Hoon MA. Cell Rep. 2019 Mar 26;26(13):3561-3573.e4. doi: 10.1016/j.celrep.2019.02.089.
 The cells and circuitry for itch responses in mice. Mishra SK, Hoon MA. Science. 2013 May 24;340(6135):968-71. doi: 10.1126/science.1233765.