New research identifies a critical inhibitory step that is a key component of the feedback circuit regulating the balance between neutrophil production and destruction.
The research, published in the March issue of Immunity, suggests that the process for disposal of dying neutrophils is actively linked to neutrophil production. A clear understanding of the processes that control neutrophil turnover may contribute to the development of future therapeutics for conditions characterized by abnormal numbers of these critical immune cells.
Human neutrophils are white blood cells that are constantly being produced in the bone marrow and released into the blood stream where they migrate out of the blood and roam the body in search of potentially harmful foreign substances. Neutrophils have a short lifespan and often die via a programmed cell death pathway called apoptosis within a matter of hours. Dying neutrophils are recognized and ingested by cells in the body tissues called phagocytes.
Although the specific mechanisms that regulate the proper ratios of neutrophil production and destruction are not well understood, it is known that the immune signaling molecules IL-17 and G-CSF stimulate neutrophil production. In addition, a newly discovered molecule called IL-23 that is produced by phagocytes has been shown to stimulate IL-17 production. Dr. Klaus Ley and colleagues from the University of Virginia investigated whether ingestion of apoptotic neutrophils influenced IL-23 production by phagocytes.
The researchers observed that the amount of IL-23 produced by phagocytes was reduced when phagocytes actively ingested apoptotic neutrophils. Interestingly, mice with abnormal neutrophils that lacked the ability to migrate into body tissues where they would have encountered phagocytes exhibited elevated IL-23 and IL-17 levels. When these mice received an infusion of normal neutrophils that were capable of migration, the levels of IL-23 and IL-17 dropped considerably.
The researchers conclude that a major mechanism for regulation of neutrophil production involves secretion of IL-23 that is regulated by phagocytosis of apoptotic neutrophils. "The discovery of neutrophil-regulating cells suggests new ways to manipulate the inflammatory system and neutrophil production with possible relevance to the treatment of inflammatory diseases and the mitigation of chemotherapy-induced neutropenia," says Dr. Ley.