Enhancing the First Responders

March 19, 2017
 The disruption of neutrophil migration upon excessive ADAM17 activity

The neutrophil is a type of white blood cell that acts as a first responder to localized bacterial infections. Neutrophils move swiftly out of blood vessels and into infected sites of the body, limit the spread of disease-causing microbes from these locations, and secrete chemical signals that call other white blood cells to clean up and repair these areas.  However, neutrophils don’t work as efficiently if bacteria enter the bloodstream and produce widespread inflammation in a condition known as sepsis, which can be deadly. A team of collaborators -  Drs. Hemant Mishra, Bruce Walcheck, and Timothy Johnson from the Department of Veterinary and Biomedical Sciences and Dr. Davis Seelig from the Department of Veterinary Clinical Sciences - discovered that an enzyme produced by neutrophils may act to impair their response during sepsis. In a study published in the Journal of Leukocyte Biology, they examined mice with a genetic deletion of ADAM17, a highly-regulated enzyme expressed by neutrophils.  ADAM17 acts like a pair of scissors and clips a variety of proteins present on the surface of neutrophils, a normal process that helps control neutrophil migration to sites of infection. During sepsis, this process occurs in an excessive manner and prevents neutrophil migration out of the blood vessels. Severe sepsis resulted in the death of normal mice within two days, but well over half the mice deficient in ADAM17 survived. In addition, a much larger number of neutrophils migrated from the blood into the site of infection, and the levels of inflammation inducing molecules in the blood were significantly lower in ADAM17-deficient mice compared to their normal counterparts.  These outcomes were not due to differences in the types of bacteria released from the intestine, but instead due to a much more efficient migration of neutrophils into the site of infection and clearance of bacteria in ADAM17-deficient mice. The research team concluded that excessive ADAM17 activity during sepsis plays a role in disrupting neutrophil migration towards sites of infection.  Could inhibitors of the ADAM17 enzyme, which are in clinical trials for cancer, enhance neutrophil migration and in turn decrease deaths from sepsis in people?

David R. Brown, Ph.D., VBS Vice chair