How does the body keep the number of neutrophils produced constant in the blood?

Mar 23 2005

Every day, the human body manufactures and destroys about 100 billion neutrophils- the most common type of white blood cell and one of the most highly-produced cells. Neutrophils live about eight hours, are bacteria-eaters and are a key component of the immune system. Without them, the body can be subject to life-threatening infection.

But how does the body keep the number of neutrophils produced constant in the blood, a mystery to scientists for decades? Researchers at the Cardiovascular Research Center at the University of Virginia Health System believe they have the answer.

They’ve discovered that these bacteria-killers in the blood are regulated by a sophisticated physiological process, much like the body’s blood pressure or water level. Their research is detailed in the March 23 issue of the journal Immunity.

Working with laboratory mice, Dr. Klaus Ley, professor of biomedical engineering at U.Va. and a U.Va. graduate student, Matthew Stark, discovered a new type of T lymphocyte, the cells that are the main means of providing the body with immune capability. This newly discovered cell, found in the lymph nodes of the gut, is called a Tn cell by Ley and Stark because it is responsible for regulating neutrophils.

“As far as we know, these primitive cells make mainly one cytokine, the protein produced primarily by white blood cells. This cytokine is IL-17,” Ley explained. “These cells are also under the control of another cytokine, IL-23. As the name suggests, these cells are responsible for regulating neutrophil numbers produced in the bone marrow. This finding will probably have significant impact not only for research, but also for clinical medicine.”

Ley said the discovery could lead to new therapies to treat neutropenia- a lack of neutrophil production that can lead to bad infections in cancer patients who undergo chemotherapy, radiation or a bone marrow transplant. The research could also be useful in treating inflammatory and autoimmune diseases, like rheumatoid arthritis or lupus, where neutrophil production may be part of the problem. “Currently, neutropenia is treated with a drug called GCSF,” Ley explained. “But it may be more beneficial in the long-run to develop drugs targeting the IL-17 cytokine.”

Ley and Stark call the process they’ve discovered the neutrophil turnstile.

“We found negative feedback,” Stark explained. “Neutrophils watch and wait for bacteria. When they find bacterial production in the gut, the body will make a cytokinethat drives neutrophil production.”

But when neutrophils die, Stark and Ley explained, they get absorbed up by other cells called macrophages and dendritic cells, downregulating their production of IL-23. That way the body can actually ‘sense’ how many neutrophils have gotten to where they need to go in the body. Stark and Ley theorize that this ‘turnstile’ is likely located in the mesenteric lymph node in the middle of the gut, and possibly the lungs and skin.

Co-authors on the Immunity paper with Ley and Stark are Yuqing Huo, Tracy L. Burcin, Margaret A. Morris and Timothy S. Olson. The research was supported by grants from the National Institutes of Health. The researchers also received invaluable assistance from U.Va.’s Flow Cytometry Core Facility.