When you prick your finger or scrape your knee, neutrophils rush to the scene. These white blood cells are the first line of defense against infection in all multicellular organisms. “They are absolutely essential for life,” says Richard Flavell, Ph.D., Sterling Professor of Immunobiology at Yale School of Medicine.
Humanized mouse models, or mice engineered to have a functional human immune system, are a valuable tool for scientists to observe immunobiology in action, but they have limitations. Despite the critical role of neutrophils, no one has been able to study them in a living context. But now, a team of Yale researchers led by Flavell has developed the first humanized mouse. model that will allow scientists to study neutrophils in vivo. The team published their findings in PNAS on October 21.
“Neutrophils are involved in almost all immune diseases,” says Esen Sefik, Ph.D., associate research scientist and collaborator on the project. “Our new model will open up many possibilities for a variety of scientists studying different diseases.”
To create a humanized mouse model, the researchers transferred stem cells in the animal that gives rise to a human-like immune system that can mimic what would happen in human bodies when pathogens are present. But in earlier mouse models, human neutrophils were unable to grow because they were overwhelmed by mouse neutrophils already present.
Human neutrophils at work in a living animal
Granulocyte colony-stimulating factor (G-CSF) is a cytokine that promotes the growth and circulation of neutrophils. The binding of G-CSF to its receptor, known as G-CSFR, stimulates this proliferation. In their new mouse model, the team first humanized the cytokine G-CSF. However, they quickly realized that this was not enough: mouse neutrophils still dominated. They then removed mouse G-CSF receptors and found that this significantly reduced the number of mouse neutrophils in the circulation and in the bone marrow.
“We found that mouse neutrophils continued to detect and respond to the human cytokine,” says Sefik. “So, we disadvantaged these neutrophils by knocking out the receptor on mouse cells that responds to G-CSF, thereby creating a deficiency in mouse neutrophils and allowing only human neutrophils to respond to G-CSF.”
With this discovery, the team wanted to make sure that human neutrophils were functional in an unflappable state. They examined their ability to respond to chemokines and express chemokine receptors, measured the production of neutrophils from reactive oxygen species, and studied their ability to create extracellular traps to capture inflammatory targets. “One by one, we looked at what the neutrophils are supposed to do and confirmed that they were operating in a steady state,” says Sefik.
Next, the team tested the ability of human neutrophils to respond to inflammation. They induced inflammation in the lung using aerosolized lipopolysaccharide (LPS), a component of certain bacteria that can create an acute inflammatory response in tissues, and found that neutrophils traveled to the lung in response. They then tested the response of neutrophils to an active infection by introducing Pseudomonas aeruginosa, a bacterium that predominantly affects immunocompromised people and is a leading cause of hospital-acquired pneumonia. They found that neutrophils could fight infection. “We showed that they have the ability to kill bacteria, which is a very important function of neutrophils,” says Sefik.
Finally, the team tested whether neutrophils could be mobilized to other parts of the body. They induced inflammation in the skin of mice and found that neutrophils mobilized there within minutes. “This shows that our findings were not just a pulmonary phenomenon and that neutrophils can lodge in any tissue,” says Sefik.
Neutrophils in COVID, cancer and beyond
The team is not only excited about their scientific achievements, but also about their ability to work together through the many obstacles presented by COVID, including the time COVID health protocols kept them out of the lab. “This is not just a good piece of science, but it’s an example of science done in the very difficult circumstances of the pandemic,” says Flavell. “The victory here is not just the science, but getting the job done under these extremely difficult circumstances. It was an achievement in itself.”
The Flavell lab’s new humanized mice are an unprecedented way to model human neutrophils in a living organism. The researchers hope that their work will lead to a greater understanding of these critics. white blood cells and its role in a wide variety of diseases. In future studies, the team hopes to study neutrophils in the context of COVID and learn more about how they might contribute to SARS-CoV-2 pathology. They also hope to learn more about the cells’ role in cancer by putting tumors in their humanized mouse models and studying the neutrophils‘ response.
Yunjiang Zheng et al, Human Neutrophil Development and Functionality Are Enabled in a Humanized Mouse Model, Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2121077119
Citation: New mouse model provides unprecedented look at human immune system (Oct 25, 2022) Retrieved Oct 25, 2022 at https://medicalxpress.com/news/2022-10-mouse-unprecedented-human- immune.html
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