Have you ever had an itchy nose or, worse yet, an unreachable spot on your back that drives you crazy? Now imagine an itch that refuses to go away, no matter how hard or long you scratch. That persistent itch, or pruritus, may actually be one of the skin’s first lines of defense against harmful invaders, according to neuroimmunologist Juan Inclán-Rico of the University of Pennsylvania.
“It is uncomfortable, annoying, but sensations like pain and itching are crucial. They are always present, especially when it comes to skin infections,” says Inclán-Rico, a postdoctoral researcher in the Herbert Laboratory of the Faculty of Veterinary Medicine of Penn. , who has been exploring what he calls “sensory immunity,” the idea that “if you can feel it, you can react to it.” Itching, he explains, is the body’s way of detecting threats like skin infections before they take hold.
But in a recent article published in nature immunologyDe’Broski Herbert, professor of pathobiology at Penn Vet, and his team turned that theory on its head. They shed light on how a parasitic worm, schistosoma mansoniIt can infiltrate the human body by evading this same defense mechanism, completely avoiding the itch response. And while there are prophylactic therapies for those who may encounter mansoniHowever, options for treating someone who has been unknowingly exposed are relatively few, and the findings of this research pave the way to address this concern.
“These blood flukes, which are among the most common parasites in humans and infect almost 250 million people, have apparently evolved to block itch, making it easier for them to enter the body undetected,” says Inclan. “So, we wanted to find out how they do it. 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 prompts us to scratch an annoying itch?”
Not all reactions are the same
Inclán-Rico says the research really began when his project revealed that certain strains of mice were more susceptible to infection by S. mansoni. “Specifically, some of the mice had a higher number of parasites that successfully passed through the entire body after penetration into the skin.”
Heather Rossi, principal investigator in the Herbert lab and co-author of the study, says this motivated the team to investigate the neural activity at play, paying special attention to MrgprA3 neurons, which are commonly associated with immunity and itch.
Then they observed how a “cousin” of mansoni that is typically found in bird species, but has been shown to cause swimmer’s itch in humans, and they found a marked difference between the reaction or lack thereof in mice.
“While avian schistosomes triggered a strong skin itch response, mansoni “We couldn’t induce this reaction,” says Rossi. “What’s more, when we introduced chloroquine, an anti-malarial drug known to cause pruritus by interacting with MrgprA3, to mice treated with mansoni antigens, we found that the itching was almost completely blocked.
A closer look
To further investigate the biochemistry involved in S. mansoni As an alternative solution to bypassing MrgprA3 neurons, the researchers employed a three-pronged strategy: using light to genetically activate neurons in the ear skin before infection, administering chloroquine, and genetically reducing the population of MrgprA3 neurons in the ear cells. mice.
“It turns out that activating these neurons blocks the input,” says Inclan-Rico. “We think it creates an inflammatory environment within the skin that prevents the entry and spread of parasites, which is particularly cool.”
Herbert Lab members (left to right): Ulrich Femoe, Heather Rossi, Adriana Stephenson, Evonne Jean, Annabel Ferguson, De’Broski Herbert, Juan Inclan Rico, Heidi Winters, Camila Napuri, Li-Yin Hung, Olufemi Akinkuotu. (Credit: Adriana Stephenson)
Herbert’s lab has been studying parasites that enter the skin, migrate through the layers of connective tissue until they find a blood vessel, and chart a course toward the lung. There they molt into another larval stage and then use the liver and portal vein to reach the intestines as adults, where they lay eggs, causing characteristic symptoms in humans such as abdominal bloating, fever and pain.
“So, as you can imagine, there are fewer parasites entering the body during the initial infection and also fewer parasites reaching the lungs,” Inclán-Rico says. “This suggests two things: that activation of these neurons blocks the entry of parasites and also inhibits their spread throughout the body.” The researchers also found that mice that had MrgprA3 ablated experienced a greater amount of lung parasite infection.
Subcellular crosstalk
Armed with the knowledge that MrgprA3 neurons were involved in blocking parasites, the team hypothesized that there might be crosstalk between these cells and immune cells, so they began investigating the relationship between these two classes.
“When we activated MrgprA3, the number of macrophages in the skin increased,” says Inclan-Rico. “These are the white blood cells that normally come in and devour infectious things, so when we depleted the macrophages, we saw that this was actually a causal relationship, that the neurons were functionally linked to the macrophage response because without them the worm infection was not blocked at all.”
Herbert’s team next sought to find the specific signaling molecules involved and discovered that upon activation of MrgprA3 the neuropeptide CGRP was released, demonstrating that this neuropeptide plays a key role in the communication between neurons and immune cells.
“CGRP acts as a messenger between neurons and macrophages,” says Inclán-Rico, “and this signaling triggers the activation of immune cells at the site of infection, which helps contain the parasite.”
However, CGRP was not acting alone, as the team discovered that the nuclear protein IL-33, normally known as an alarm signal released by damaged cells, played a surprising and significant role. When they examined macrophages, they discovered that IL-33 was not only reduced but acted within the cell nucleus.
“Until now, people thought that IL-33 was a nuclear protein, but we didn’t know exactly what it did there. It was more thought that its role was as a secreted factor, or as a consequence of cell death. or potentially of cells. that secrete it directly,” says Rossi. “But we did a series of experiments to show that, in fact, IL-33 in macrophages controls DNA accessibility, essentially opening up the tight packaging material of DNA and allowing proinflammatory cytokines like TNF to be expressed.”
This pro-inflammatory environment is essential to form a protective barrier that prevents the parasite from advancing further into the body.
“It’s a two-step process,” says Inclán-Rico. “First, MrgprA3 neurons release CGRP, which signals to macrophages. Then, IL-33 contained within macrophage nuclei is greatly reduced, which enhances the inflammatory response and helps block parasite entry.”
Interestingly, they also found that when IL-33 was genetically deleted from macrophages, the protective response induced by spiking neurons was lost.
“This tells us that neurons are orchestrating all of this defense, but they need macrophages, and specifically IL-33 in those macrophages, to generate a full immune response,” says Herbert.
Looking ahead, the Herbert laboratory plans to further understand the mechanisms behind this communication between neurons and immunity.
“We’re really interested in identifying the molecules that parasites use to suppress neurons and whether we can harness that knowledge to block parasite entry more effectively,” says Herbert. They also hope to identify other molecules, in addition to CGRP and IL-33, that are involved in this signaling pathway.
“If we can identify the exact components that parasites target 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, such as eczema or psoriasis,” says Herbert.
De’Broski R. Herbert is Presidential Professor of Immunology and Professor of Pathobiology at the University of Pennsylvania School of Veterinary Medicine.
Juan Manuel Inclán-Rico is a postdoctoral researcher at Penn Vet’s Herbert Laboratory.
Heather L. Rossi is a principal investigator at Penn Vet’s Herbert Laboratory.
Other researchers include Ulrich M. Femoe, Annabel A. Ferguson, Bruce D. Freedman Li-Yin Hung, Xiaohong Liu, Fungai Musaigwa, Camila M. Napuri, Christopher F. Pastore and Adriana Stephenson of Penn Vet; Wenqin Luo and Qinxue Wu of Penn’s Perelman School of Medicine; Cailu Lin and Danielle R. Reed of the Monell Chemical Senses Center; Petr Horák and Tomáš Macháček from Charles University, Czech Republic; and Ishmail Abdus-Saboor of Columbia University.
The research was supported by the National Institutes of Health (grants T32 AI007532-24, R01 AI164715-01, U01 AI163062-01, P30-AR069589 and R01 AI123173-05 and contract HHSN272201700014I), Charles University (Cooperatio Biology, UNCE24/SCI /011, SVV 260687) and the Czech Scientific Foundation (GA24-11031S).