Abstract
FOXO transcription factors have a highly conserved role in regulating transcription of genes involved in differentiation, cell cycle arrest, apoptosis and DNA repair. Loss of FOXO3 in mice has previously been shown to result in a myeloproliferative disease. In agreement with this, we found that an independent Foxo3 null mouse strain, Foxo3 Kca, exhibits an increase in neutrophils in the spleen, bone marrow and blood. This coincides with an expansion of myeloid progenitor cells including pre-granulocyte-macrophage progenitors (Pre-GMs) and granulocyte-macrophage progenitors (GMPs). Surprisingly, despite neutrophilia, the severity of passive serum transfer arthritis was markedly attenuated in Foxo3 Kca mice. These defects appear to be at least partially intrinsic to the myeloid lineage, as deleting Foxo3 specifically from myeloid cells using LysMCre also leads to an elevated number of neutrophils and protection from K/BxN-serum transfer-induced arthritis.
Highlights
FOXO transcription factors integrate a wide variety of signals to control diverse physiologic processes such as differentiation, cell cycle arrest, apoptosis, metabolism, and detoxification of reactive oxygen species (ROS) [1]
Foxo3Trap mice were found to be resistant to inflammation in two neutrophil-dependent inflammatory models including K/BxN-serum transfer arthritis
Several studies have reported that FOXO3 is important for neutrophil homeostasis
Summary
FOXO transcription factors integrate a wide variety of signals to control diverse physiologic processes such as differentiation, cell cycle arrest, apoptosis, metabolism, and detoxification of reactive oxygen species (ROS) [1]. FOXO transcription factors have been implicated in the control of hematopoiesis [2]. Acute disruption of the genes encoding all three of the peripheral Foxo transcription factors (Foxo, Foxo and Foxo4) has broad consequences on hematopoiesis including: reduced size of the hematopoietic stem cell (HSC) and lymphoid progenitor compartments, but increased myeloid colony formation potential and number of neutrophils in the spleen. The loss of HSCs in this model was found to be associated with increased ROS, leading to increased cycling and apoptosis of HSCs, and was corrected by administration of an antioxidant [2].
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