New Mouse Model Provides Unprecedented Look at Human Immune System

On the prick of a finger or a scratch on the 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, PhD, Sterling Professor of Immunobiology at Yale School of Medicine.

Humanized mouse models, or mice engineered to have a functioning 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 implicated in almost all immunological diseases,” says Esen Sefik, PhD, research associate and collaborator on the project. “Our new model will open up many possibilities for a range of scientists studying different diseases.”

To create a humanized mouse model, researchers transfer progenitor cells into the animal that give rise to a human-like immune system that can mimic what would happen in the body of human beings when pathogens are present. But in previous mouse models, human neutrophils were unable to grow because they were overtaken by mouse neutrophils already present.

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Functioning of human neutrophils 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, called G-CSFR, stimulates this proliferation. In their new mouse model, the team first humanized the cytokine G-CSF. However, they quickly realized that was not enough: mouse neutrophils continued to dominate. Next, they removed mouse G-CSF receptors and found that this significantly reduced the number of mouse neutrophils in circulation and in the bone marrow.

“We realized that mouse neutrophils still detected and responded to the human cytokine,” says Sefik. “So we disadvantaged these neutrophils by deleting the receptor on mouse cells that responds to G-CSF, thereby creating a mouse neutrophil deficiency and allowing only human neutrophils to respond to G-CSF.”

With this discovery, the team wanted to ensure that human neutrophils were functional in an undisturbed state. They examined their ability to respond to chemokines and express chemokine receptors, measured the production of reactive oxygen species by neutrophils, and studied their ability to create extracellular traps to capture inflammatory targets. “One by one, we looked at what neutrophils are supposed to do and confirmed that they work in a stable state,” says Sefik.

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Next, the team tested the ability of human neutrophils to respond to inflammation. They induced inflammation in the lungs using aerosolized lipopolysaccharides (LPS), a component of certain bacteria that can create an acute inflammatory response in the tissues, and they found that neutrophils travel to the lungs in response . They then tested the neutrophil response to active infection by introducing Pseudomonas aeruginosa, a bacterium that mainly affects immunocompromised people and is one of the main causes of nosocomial pneumonia. They discovered that neutrophils were able to 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 mobilize to other parts of the body. They induced inflammation in the skin of mice and found that neutrophils mobilized there within minutes. “It shows that our findings were not just a lung phenomenon and that neutrophils can harbor any tissue,” says Sefik.

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Neutrophils in COVID, Cancer and Beyond

The team is not only excited about their scientific accomplishments, but also about their ability to work together through the many obstacles presented by COVID, including when COVID health protocols kept them out of the lab. “It’s not only beautiful science, but it’s an example of science being done under the very difficult circumstances of the pandemic,” Flavell says. “The victory here is not just the science, but the achievement of the work under these extremely difficult circumstances. That was a feat in itself.”

The new humanized mice from the Flavell lab are an unprecedented way to model human neutrophils in a living organism. The researchers hope their work will lead to a better understanding of these critical white blood cells and their 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 role of cells in cancer by putting tumors in their humanized mouse models and studying the neutrophil response.

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