IMMUNOLOGY Maintaining a Steady Supply

Although the number of neutrophils circulating in blood is maintained relatively constant, the mechanisms through which production is increased under neutropenic conditions or decreased under neutrophilic conditions remain unclear. IL-23, a cytokine produced by dendritic cells (DCs) and macrophages (Ms), stimulates T cells to produce interleukin-17 (IL-17), which stimulates neutrophil production. Noting that strains of mouse that lack adhesion molecules (which have defects in neutrophil trafficking) exhibit neutrophilia, Stark et al. hypothesized that DCs and Ms--which phagocytose apoptotic neutrophils--monitor the numbers of neutrophils reaching peripheral tissues and provide a feedback mechanism to regulate production. Fluorescent labeling revealed that wild-type neutrophils were more likely to undergo phagocytosis than were those from CD18^–/– mice when injected into the same recipient mice. In mice that lacked CD18 or the endothelial selectins (which were neutrophilic), IL-17 mRNA abundance in mesenteric lymph nodes (MLN), spleen, and elsewhere was increased, as was the percentage of total T cells that produced IL-17. Bone marrow-derived dendritic cell (BMDC)-conditioned medium stimulated production of IL-17 by CD18^–/– splenocytes, as did M-conditioned medium, an effect that was blocked by an antibody to the p40 subunit of IL-23 and attenuated by coculturing the BMDCs or Ms with apoptotic neutrophils. Adoptive transfer of wild-type but not CD18^–/– neutrophils into CD18^–/– mice reduced the enhanced expression of IL-23 in MLN, as well as the numbers of circulating neutrophils and the serum IL-17 concentration; moreover, antibody to the p40 subunit of IL-23 reduced the numbers of circulating neutrophils. Thus, the authors propose that neutrophil phagocytosis--and a consequent decrease in IL-23 production--acts as a negative feedback mechanism to regulate neutrophil production.

M. A. Stark, Y. Huo, T. L. Burcin, M. A. Morris, T. S. Olson, K. Ley, Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 22, 285-294 (2005). [PubMed]