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Experiencing an itch can be frustrating, especially when it’s located in hard-to-reach areas of the body. However, researchers are uncovering that persistent itching, or pruritus, may serve as a crucial biological mechanism in defending the skin against potential threats. According to neuroimmunologist Juan Inclan-Rico of the University of Pennsylvania, this phenomenon is more than just an annoyance; it plays a significant role in alerting the body to harmful invaders, such as pathogens.
Inclan-Rico, a postdoctoral researcher in the Herbert Lab at Penn’s School of Veterinary Medicine, emphasizes that sensations like pain and itchiness are key indicators of immune responses, particularly concerning skin infections. He describes the itch as a means of detecting threats early on, prompting necessary defensive actions before a full-blown infection can develop.
In a recent publication in Nature Immunology, professor De’Broski Herbert and his research team challenged the conventional view of the itch response. Their study reveals how the parasitic worm Schistosoma mansoni manages to enter the body by circumventing the very itch response that typically alerts the immune system. While there are preventative treatments for potential exposures to S. mansoni, effective therapeutic options for individuals who have already been unknowingly infected remain limited. These findings could inform future approaches to addressing such infections more effectively.
“These blood flukes are among the most widespread parasites infecting humans, with nearly 250 million cases reported globally. They’ve evolved mechanisms to disable the itch response, facilitating their entry into the body without detection,” Inclan-Rico states. The research team aimed to uncover the molecular processes through which these parasites efficiently inhibit this vital sensory alarm and what these insights could reveal about the biological mechanisms that compel scratching.
Uncovering Susceptibility
The research initiative gained momentum when Inclan-Rico’s findings indicated that certain mouse strains exhibited higher susceptibility to S. mansoni infections, with some strains displaying significantly more parasites after skin exposure.
Heather Rossi, a senior research investigator in the Herbert lab and co-author of the study, notes that this observation spurred the team to delve into the neuronal activities involved, particularly focusing on MrgprA3 neurons, which are heavily implicated in itch sensation and immune responses.
The team then conducted comparative analyses using a related schistosome species commonly found in birds, which causes swimmer’s itch in humans. They observed a marked difference in the itching response from the mice, revealing that while the avian schistosomes prompted a vigorous itch, S. mansoni effectively dulled this sensory alert.
“Introducing chloroquine, an anti-malarial that induces itching via MrgprA3 interaction, into mice treated with S. mansoni antigens substantially inhibited the itch response,” Rossi explains.
Investigating the Mechanisms
To gain a deeper understanding of how S. mansoni evades the scrutiny of MrgprA3 neurons, the researchers adopted a three-pronged approach: they utilized light to activate specific neurons in the skin prior to infection, administered chloroquine, and genetically altered the mouse models to reduce the number of MrgprA3 neurons.
The results were intriguing; activating these neurons seemingly prevented the entry of the parasites, creating an inflammatory response within the skin that acted to block infection. “What this reveals is quite remarkable,” Inclan-Rico adds.
The team outlined the life cycle of the parasites, detailing how they penetrate the skin, navigate through connective tissues, and ultimately find their way into the bloodstream and other organs, resulting in debilitating symptoms like abdominal swelling and fever.
“Fewer parasites entering the body suggests that neuron activation not only inhibits their immediate entry but also curtails their capacity to spread within the host,” Inclan-Rico explains. Moreover, they noted that mice lacking MrgprA3 showed heightened lung infection rates from the parasites.
The Role of Cell Communication
Given that MrgprA3 neurons were identified as critical in thwarting parasite entry, researchers sought to explore the interplay between these neurons and immune cells, particularly macrophages. “We observed that when we activated MrgprA3, the number of macrophages in the skin increased,” Inclan-Rico shares. This connection led to the conclusion that neuronal responses were closely linked to macrophage activity in combatting infections.
Following this, the researchers investigated specific signaling molecules and discovered that activation of MrgprA3 led to the release of the neuropeptide CGRP, highlighting its importance in neuron-immune cell communication.
“CGRP functions as a signaling messenger between neurons and macrophages, triggering immune cell activation at the infection site,” Inclan-Rico clarifies. However, CGRP’s role was not isolated; the researchers also noted the influence of IL-33, a nuclear protein typically known as a damage signal. Findings revealed that IL-33’s presence within the macrophages was critical for the inflammatory response, as it modulated DNA accessibility to promote pro-inflammatory cytokine expression.
This process is vital for establishing a protective barrier against advancing parasites.
“The mechanism operates in a two-step manner,” Inclan-Rico notes. “First, MrgprA3 neurons generate CGRP, which influences macrophages. Next, IL-33’s reduction within these cells amplifies the inflammatory response, effectively blocking the parasites.” When IL-33 was genetically removed from macrophages, the neuronal-mediated protective response was markedly diminished.
“This indicates that while the neurons orchestrate the immune defense, they rely on collaborating with macrophages, particularly through IL-33, to mount a comprehensive immune reaction,” Herbert asserts.
Looking to the future, the Herbert laboratory aims to delve more thoroughly into the mechanisms underlying neuron-immune communication.
“Our goal is to identify the molecules that parasites deploy to suppress neuronal activity and explore the potential to leverage this information to disrupt parasite entry,” Herbert explains. The team is also interested in identifying additional signaling components aside from CGRP and IL-33 involved in this pathway.
“Identifying the precise elements that parasites exploit to evade the itch response could lead to innovative therapeutic strategies that address parasitic infections and relieve conditions characterized by itchiness, such as eczema or psoriasis,” Herbert concludes.
De’Broski R. Herbert is a presidential professor of immunology and a professor of pathobiology at the University of Pennsylvania’s School of Veterinary Medicine.
Juan Manuel Inclan-Rico is a postdoctoral researcher in the Herbert Lab at Penn Vet.
Heather L. Rossi is a senior research investigator in the Herbert Lab at Penn Vet.
The research team includes 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, along with colleagues from the Perelman School of Medicine at Penn, the Monell Chemical Senses Center, and other institutions.
This research was supported by the National Institutes of Health and other funding sources.
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