New mouse model offers unprecedented view of the human immune system

When a knuckle or knee is scratched, 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 to life,” says Richard Flavell, PhD, professor of immunobiology at Yale School of Medicine.

Clone mouse models, or mice engineered to have a functional human immune system, are a valuable tool for scientists to observe immune biology in practice, but they have limitations. regime. Despite the important role of neutrophils, no one has yet been able to study them in the context of life. But now, a team of Yale researchers led by Flavell has developed the first cloned mouse model that would allow scientists to study neutrophils in vivo. The group published its findings in PNAS on October 21.

Dr Esen Sefik, research scientist and project collaborator, said: “neutrophils are implicated in almost every immune pathology. “Our new model will open up many possibilities for a wide range of scientists studying different diseases.”

To create a humanized mouse model, the researchers progenitor cells into animals gives rise to a human-like immune system that can mimic what happens in the human body when pathogens are present. But in previous mouse models, human neutrophils could not grow because they were overwhelmed by already existing mouse neutrophils.

Activity of human neutrophils in live animals

Granulocyte colony-stimulating factor (G-CSF) is a cytokine that promotes neutrophil growth and circulation. 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 this was not enough – the mouse neutrophils continued to dominate. Next, they removed the mice’s G-CSF receptors and found that this significantly reduced the rat’s neutrophils in the circulation and in the bone marrow.

“We realized that the mouse neutrophils were still detecting and responding to human cytokines,” says Sefik. “So we disadvantaged these neutrophils by knocking out the receptor on mouse cells that respond to G-CSF, thereby creating a deficiency in mouse neutrophils and only allows human neutrophils to respond to G-CSF. “

With this discovery, the team wanted to ensure that human neutrophils function in an undisturbed state. They looked at chemokine responsiveness and chemokine receptors expression, measuring neutrophil production reactive oxygen species, and investigated their ability to generate extracellular traps for the capture of inflammatory targets. “One by one, we looked at what the neutrophils were supposed to do and confirmed that they were functioning at steady state,” says Sefik.

Next, the team examined the ability of human neutrophils to respond to inflammation. They induced inflammation in the lungs using aerosolized lipopolysaccharide (LPS), a component of some bacteria that can induce an acute inflammatory response in tissues, and they found that white blood cells neutrophils migrate to the lungs in response. They then tested the neutrophil response to an active infection by introducing Pseudomonas aeruginosa, a bacterium that mainly affects immunocompromised people and is one of the leading cause of hospital-acquired pneumonia. They found that neutrophils can fight infections. “We have shown 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 caused inflammation in the skin of the mice and found that the neutrophils would mobilize there within minutes. “This shows that our findings are not just a lung phenomenon, and that neutrophils can be home to any tissue,” says Sefik.

Neutrophils in COVID, cancer and more

The team is not only excited about their scientific achievements, but also their ability to work together to overcome many of the obstacles that COVID presents, including the time that COVID health protocols have kept them apart. out of the laboratory. “This is not only a great piece of science, but also an example of science being done under very difficult circumstances during the pandemic,” Flavell said. “Winning here isn’t just about science, it’s about getting the job done under these extremely difficult circumstances. That’s an achievement in itself.”

Flavell labs new cloned mice are an unprecedented way to model human neutrophils in a living organism. The investigators hope their work will allow for a better understanding of the White blood cells and their role in many diseases. In future studies, the team hopes to study neutrophils in the context of COVID and learn more about how they may contribute to SARS-CoV-2 pathology. They also hope to learn more about the role of cells in cancer by inserting tumors into their cloned mouse models and studying them. neutrophil‘ react.