UC San Diego

Foxo transcription factors are critical mediators and have a highly conserved role in regulating hematopoietic homeostasis by limiting physiologic oxidative stress. A loss in Foxo3 causes a striking myeloproliferation, induced in part by increased accumulation of reactive oxygen species (ROS), that amplifies that Akt/mTOR signaling pathway. Here we found that a Foxo3-deficient mouse strain, Foxo3/Lex, exhibited increased neutrophil production from an expansion of myeloid progenitor cells: CMPs, Pre GMs, and GMPs. Such neutrophilia and increase in progenitor cells were more apparent and exaggerated in the spleen, in comparison to the BM of Foxo3/Lex mice. Interestingly, although neutrophils are known to exaggerate conditions of neutrophilic inflammation, Foxo3/ Lex mice, exhibited normal conditions of peritonitis and reduced severity of rheumatoid arthritis despite their increased neutrophil numbers. The increase in splenic neutrophils also compelled us to examine their possible novel role as B cell-helper neutrophils, which have been recently identified as neutrophils in the marginal zone of the spleen that activate B cells to generate an antimicrobial immunoglobulin defense. In conclusion, Foxo3 appears to regulate and promote the proper balance of neutrophil populations to avoid overproduction possibly from exaggerated granulopoiesis, especially in the spleen