Have you ever felt irritated by an itchy nose, or worse, an area on your back that you can’t reach? Now, imagine an itch that just won’t go away no matter how hard you scratch or how long you scratch it. Please try it. That persistent itching, or itching, may actually be one of the skin’s first lines of defense against harmful invaders, says neuroimmunologist Juan Inclan Rico of the University of Pennsylvania. .
“Although they are inconvenient and bothersome, sensations like pain and itching are very important. They are always present, especially when it comes to skin infections,” said Incran Rico, a postdoctoral researcher in Herbert’s lab at the Penn State School of Veterinary Medicine. he says. He has been studying what he calls “sensory immunity,” the idea that “if you can feel it, you can respond to it.” Itching, he says, is the body’s way of detecting threats such as skin infections before they take hold.
But in a recent paper published in Nature Immunology, Debrosky Herbert, a professor of pathobiology at the Pennsylvania College of Veterinary Medicine, and his team turned that theory on its head. They revealed how the parasite Schistosoma mansoni is able to invade the human body by evading this very defense mechanism and completely avoiding the itch response. Additionally, although preventive treatments exist for people who may have encountered Schistosoma mansoni, there are relatively few treatment options for those who have unknowingly been infected, and these findings raise concerns. This paves the way for dealing with
These flukes, one of the most prevalent parasites in humans, infecting around 250 million people, appear to have evolved to block the itch, allowing them to enter the body undetected. It’s easier to break into. So we wanted to know how they do it. What are the underlying molecular mechanisms for how we disarm these important sensory alarms? And what does this tell us about the sensory organs that make us scratch that pesky itch? Do you want it?”
Inclan-Rico, Postdoctoral Researcher, Herbert Laboratory, Pennsylvania College of Veterinary Medicine
Not all reactions are the same
Inclan-Rico said research began in earnest when his project revealed that certain strains of mice were more susceptible to infection with Schistosoma mansoni. “Specifically, in some mice, more parasites were able to successfully pass through the body after entering the skin.”
Heather Rossi, a senior researcher in Herbert’s lab and co-author of the study, said this led the team to study actual neuronal activity, paying special attention to the MrgprA3 neuron, which is commonly associated with immunity and itch. He said it motivated him to investigate.
Next, we investigated that a “cousin” of Schistosoma mansoni, which is typically found in birds, is known to cause swimmer’s itch in humans. I discovered that there is a difference.
“While the avian Schistosoma caused a strong itching reaction in the skin, the Schistosoma mansoni was unable to induce this response,” Professor Rossi said. “Furthermore, when we introduced chloroquine, an antimalarial drug known to cause itch by interacting with MrgprA3, to mice treated with Schistosoma mansoni antigen, we found that itch was almost completely blocked. got it.”
See more details
To further investigate the biochemistry involved in Schistosoma mansoni’s evasion strategy to avoid MrgprA3 neurons, the researchers adopted a tripod strategy. The idea is to genetically activate neurons in the ear skin using light and administer chloroquine before infection to genetically reduce the number of MrgprA3 neurons. Among the rats.
“We found that activating these neurons blocks invasion,” Incran-Rico says. “We think it creates an inflammatory environment within the skin that prevents parasites from entering and spreading, which is particularly exciting.”
Members of the Herbert lab (from left to right): Ulrich Femo, Heather Rossi, Adriana Stevenson, Evonne Jean, Annabelle Ferguson, Debroski Herbert, Juan Incran Rico, Heidi Winters, Camila Napry, Lee Yin Hung, Olufemi Akikuothu. (Credit: Adriana Stevenson)
Herbert’s lab has been studying parasites that invade the skin, travel through layers of connective tissue until they find blood vessels, and chart a course toward the lungs. There they molt into another larval stage, then progress to the intestine as an adult via the liver and portal vein, where they lay eggs and cause characteristic human symptoms such as abdominal swelling, fever, and pain.
“As you can imagine, the fewer parasites that enter the body during the initial infection, the fewer parasites that enter the lungs,” Professor Incran-Rico says. “This suggests two things: the activation of these neurons is blocking parasite entry, and it is also blocking the spread of the parasite into the body. ” The researchers also found that mice in which MrgprA3 was deleted had increased amounts of lung parasite infections.
intracellular crosstalk
With the knowledge that MrgprA3 neurons are involved in stopping parasites, the team hypothesized that there might be crosstalk between these cells and immune cells, and investigated the relationship between these two classes. I started investigating.
“Activating MrgprA3 increased the number of macrophages in the skin,” says Inclan-Rico. “These are white blood cells that normally invade and devour infectious elements, and when we depleted the macrophages, we found that this was indeed a causal link, and that neurons were functionally linked to the macrophage response. The worm infection was not blocked at all.
The Herbert team then sought to find the specific signaling molecules involved and discovered that downstream of MrgprA3 activation, the neuropeptide CGRP is released, and that this neuropeptide is important in neuron-immune cell communication. It has been demonstrated that it plays a role.
“CGRP acts like a messenger between neurons and macrophages, and this signaling triggers the activation of immune cells at the site of infection, which helps contain the parasite,” says Dr. Incran Rico.
But CGRP does not work in isolation; the researchers discovered that the nuclear protein IL-33, known as an alarm signal normally released by damaged cells, plays a surprisingly important role. Ta. When they examined macrophages, they found that not only was IL-33 reduced, but that it was acting within the cell nucleus.
“Until now, people only thought that IL-33 was a nuclear protein, but they didn’t know exactly what it was doing inside. Its role may be due to cell death or “It was more likely that it was a secreted factor,” or it could be secreted directly by immune cells, Rossi said. “But IL-33 in macrophages actually controls DNA accessibility, essentially opening up the dense packaging of DNA and allowing the expression of pro-inflammatory cytokines like TNF. We conducted many experiments to prove this.”
This pro-inflammatory environment is important for forming a protective barrier that prevents parasites from further invading the body.
“This is a two-step process,” Incranrico said. “First, MrgprA3 neurons release CGRP, which signals macrophages. Subsequently, IL-33 retained within the macrophage nucleus is significantly reduced. This enhances the inflammatory response and It helps prevent intrusion.”
Interestingly, they also found that when IL-33 was genetically deleted from macrophages, the protective response elicited by itchy neurons was lost.
“This shows that neurons orchestrate this entire defense, but that they require macrophages, especially IL-33 within macrophages, to mount a full immune response,” Herbert says.
Looking ahead, the Herbert lab plans to further understand the mechanisms behind this neuron-immune communication.
“We are very interested in identifying the molecules that the parasite uses to suppress neurons and whether we can use that knowledge to more effectively block parasite invasion.” Herbert says. They also hope to identify other molecules involved in this signaling pathway, beyond CGRP and IL-33.
“If we can identify the exact ingredients that parasites target to avoid an itch response, we have the potential to not only treat parasitic infections, but also provide relief from other itch-related conditions such as eczema and psoriasis.” “We have the potential to develop new therapeutic approaches,” Herbert said.
sauce:
university of pennsylvania
Reference magazines:
Inclan-Rico, J.M., et al. (2024). MrgprA3 neurons drive cutaneous immunity against helminths through selective regulation of bone marrow-derived IL-33. Innate immunology. doi.org/10.1038/s41590-024-01982-y.
