UNIVERSITY PARK, Pa. -- One of the body's tools for fighting off infection in a wound may actually slow down the healing process, according to new research by a team of Harvard University, Boston Children's Hospital, and Penn State University scientists. In a study published online in Nature Medicine on June 15, 2015, the researchers show that they can speed up wound healing in diabetic mice by preventing immune cells called neutrophils from producing structures called NETs (neutrophil extracellular traps) that trap and kill bacteria.
"In the fight against bacterial infection, NETs cause collateral damage that slows healing," said Yanming Wang, associate professor of biochemistry and molecular biology at Penn State and a member of the research team.
NETs are thought to reduce the risk of infection in a wound but they also form a dense, toxic mesh that interferes with the mobilization of new healthy cells and hinders tissue repair. The process is even more of a problem in individuals with diabetes, whose neutrophils produce more NETs. As a result, delayed wound healing is a common complication of both type 1 and type 2 diabetes.
To see how diabetes increases a neutrophil's ability to produce NETs, the researchers examined neutrophil cells from patients with either type 1 or type 2 diabetes. They found that these neutrophil cells contained four times the normal amount of the PAD4 enzyme -- a protein that catalyzes the production of NETs. Further experiments revealed that neutrophils from healthy donors or mice that were exposed to excessive glucose -- mimicking diabetes -- also were more likely to release NETs than neutrophils that were exposed to normal glucose levels.
Diabetic mice in the study had more NETs in wounds and healed more slowly than normal mice. However, when the team examined diabetic mice that lacked the PAD4 enzyme they found that the wounds of these mice healed more quickly. "Neutrophils of individuals with diabetes are primed to form NETs by high levels of PAD4, but when we eliminate or control the expression of the PAD4 enzyme in mice with diabetes, we can prevent NETs from forming and speed up healing," Wang said. "It remains to be tested if pharmacological intervention of PAD4 activity will benefit the healing process."