Researchers at the University of Toronto Faculty of Dentistry have discovered something about neutrophils, the most numerous white blood cells in the body, that may lead to new models for diagnosing and tracking inflammatory diseases such as cancer and osteoarthritis.
Neutrophils are the body’s “first responders” and a class of leukocyte immune cell in the “innate” immune system, which deals with acute infections. Billions of neutrophils are born in bone marrow each day to protect the body and attack microbial invaders.
“The general consensus in the past was that there is one kind of neutrophil in circulation in healthy people,” said Michael Glogauer, DDS, PhD, author of the study and a professor with the Faculty of Dentistry and acting chief dentist at the Princess Margaret Cancer Centre.
“We found two distinct neutrophil states in blood, and these populations vary depending on the health of the patient and if there are acute or chronic infections,” said Glogauer.
The researchers discovered this unique subset of immune cells after developing a method for preserving and analyzing neutrophils in blood, overcoming a longstanding difficulty in how to study these short-lived and easily activated immune cells.
Primed neutrophils (pPMNs) are in a state of constant readiness to fight infections, making up to 10% of the overall neutrophil population. The more abundant “resting state” neutrophils (rsPMNs) circulate in the blood in a naïve state.
The researchers then tested blood samples from mice with acute infections and from humans with chronic gingivitis, tracking the prime and resting neutrophils. When an acute infection flares up, the pPMNs quickly leave the blood stream and enter the tissues.
In mouse and human models with acute inflammation, the primed cells disappear from the bloodstream and enter inflamed tissues within 15 minutes. Within one to three hours, the remaining rsPMNs also become activated and follow the pPMNs into the tissues.
“The current paradigm is that neutrophils are circulating in the blood, just waiting for something to happen, and then they are immediately recruited into tissue and fight infection,” said Noah Fine, PhD, MS, first author and a postdoctoral fellow with the Faculty of Dentistry.
“That’s still true,” said Fine, “but we’re now looking at a model with a fine-tuned mechanism. In this model, the neutrophils aren’t constantly on a knife’s edge, waiting to react to an infection. That could lead to overexuberant neutrophil responses in healthy individuals.”
The discovery may aid in disease detection and monitoring. If the percentage of pPMNs in the blood is constant in a healthy state, hovering around 10%, “we can track the state of the activation of the innate immune system where the expectation would be elevated levels of this primed population,” said Glogauer.
Blood samples from those who are experiencing inflammatory disease attacks, for instance, can be examined for the number of pPMNs as a barometer of the activation state of the immune system, telling clinicians exactly how acute an infection is across a wide range of inflammatory diseases such as cancer, gout, arthritis, and diabetes.
The researchers are now testing neutrophil populations both just before and after cardiovascular surgery, as well as patients with rheumatoid arthritis and periodontitis. The discovery also may lead to new paradigms for health research, the researchers said.
“The fact that we see this population in mice and that it appears to behave similarly in humans is very exciting,” said Fine, who added that mice and other animal models used in health research sometimes have limitations based on their differences with humans. The neutrophil populations, in contrast, appear to be similar across mammals, the researchers said.
The study, “Primed PMNs in Healthy Mouse and Human Circulation Are First Responders During Acute Inflammation,” was published by Blood Advances.
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