Having an itch that you just can’t scratch is one of the most frustrating experiences – but it might actually be beneficial in the long run, according to scientists from the University of Pennsylvania.
“That persistent itch, or pruritus, may actually be one of the skin’s first lines of defense against harmful invaders,” said a press release from the university citing neuroimmunologist Juan Inclan-Rico. He’s a postdoctoral researcher in the Herbert Lab at Penn’s School of Veterinary Medicine and part of a team that published a recent paper on the topic in the Nature Immunology journal.
According to the Cleveland Clinic, pruritus can have many causes. Some of the most common are allergens, dry skin, pregnancy and reactions to medication. Sometimes, the location of the itch may indicate its cause – for example, upper arm itching can be associated with brachioradial pruritus caused by nerve damage.
Inclan-Rico said itching is also one pf the ways the body detects threats such as skin infections.
“It’s inconvenient, it’s annoying, but sensations like pain and itch are crucial. They’re ever-present, especially when it comes to skin infections,” he said. Inclan-Rico calls the reaction a type of “sensory immunity,” a way that the body can sense skin infections before they take hold.
To learn more about the function of itching, Penn Today’s team of researchers – led by pathobiology professor De’Broski Herbert – looked at a case in which the reaction fails to alert humans of a threat. When the Schistosoma mansoni parasitic worm sneaks into the body, it bypasses the human urge to itch and other defense mechanisms.
Without the urge to itch, patients can unknowingly become exposed to the parasite, which the U.S. Centers for Disease Control and Prevention said is found primarily across sub-Saharan Africa, Brazil, Venezuela, Suriname, the Caribbean and occasionally in the Arabian Peninsula. Once an individual has been exposed to it, there are “relatively scant” treatment options, said Penn Today.
Every year, nearly 250 million people are infected with these blood flukes, making them one of the most prevalent parasites in humans, Inclan-Rico said.
“We wanted to figure out how they do it [block the itch],” said the researcher. “What are the molecular mechanisms underlying how they turn off such an essential sensory alarm? And what can this teach us about the sensory apparatus that drives us to scratch a pesky itch?”
When the team observed that some mice were more susceptible to S. mansoni infection, they were inspired to investigate how neuronal activity might be at play, explained Heather Rossi, a senior research investigator in the Herbert lab and co-author on the study. They focused on MrgprA3 neurons that are commonly associated with immunity and itchiness.
Then they compared S. mansoni to a similar parasite that can cause swimmer’s itch in humans. This comparison revealed stark differences. It even showed that mice infected with S. mansoni had less itching when exposed to chloroquine, an anti-malarial drug that usually triggers itching.
Researchers also studied what happened when MrgprA3 neurons in mice were activated with light prior to infection with S. mansoni.
“Turns out that activating these neurons blocks the entry,” Inclan-Rico says. “It creates an inflammatory environment, we think, within the skin that prevents the entry and dissemination of the parasites, which is particularly cool.”
If these parasites successfully enter the skin, they can make their way to a blood vessel, travel to the lung and molt into another larval stage and eventually lay eggs in the intestine. At that point, infected humans can experience abdominal swelling, fever, and pain.
After they figured out that the “itchy” MrgprA3 neurons helped block the entry of parasites, the researchers started to look onto possible “crosstalk” between those cells and immune cells. This research uncovered a link – activated MrgprA3 cells resulted in an increased number of macrophages in the skin.
“These are the white blood cells that typically come in and gobble up infectious elements, and so, when we depleted the macrophages, we saw that this was in fact a causal relationship, that the neurons were functionally linked to the macrophage response because without them the worm infection wasn’t blocked at all,” Inclan-Rico explained.
Additionally, the researchers found that “downstream of MrgprA3 activation the neuropeptide CGRP was released, demonstrating that this neuropeptide plays a key role in neuron-immune cell communication,” according to Penn Today. The CGRP neuropeptide acts as a messenger that helps trigger the activation of immune cells. Nuclear protein IL-33, also appears to be part of the parasite alert system.
“Up until now, people just thought that IL-33 was a nuclear protein, but we didn’t know exactly what it was doing in there. Its role was more thought to be as a secreted factor, either as a consequence of cell death or potentially from immune cells secreting it directly,” Rossi said. “But we did a number of experiments to prove that, in fact, IL-33 in macrophages controls the accessibility of DNA, essentially opening DNA’s tight packaging material and allowing pro-inflammatory cytokines like TNF to be expressed.”
What that means is that the protein plays a role in creating an inflammatory environment that acts as a protective barrier against parasites. Furthermore, the team found that when IL-33 was genetically deleted from macrophages, the protective response linked to “itchy” neurons was lost.
Going forward, Herbert hopes to continue research into the role itching plays in fighting off infections.
“If we can pinpoint the exact components that parasites are targeting to evade the itch response, we could develop new therapeutic approaches that not only treat parasitic infections but potentially offer relief for other itch-related conditions like eczema or psoriasis,” Herbert said.