IFNy Regulates the Balance Between Monocyte and Neutrophil Production During Immune Activation.

Abstract 1562

Recruitment of the appropriate cells from the innate immune system to sites of infection is essential for the defense against pathogens. Depending on the type of invading pathogen, infection induces a rapid release from innate immune cells from the bone marrow, followed by an increased production of those myeloid cells that are most suitable to assist the ensuing immune response in the rapid eradication of the pathogen. However, it is thus far poorly understood what the cellular and molecular mechanism is that underlies this change in hematopoiesis.

Using a mouse model with increased numbers of IFNγ-producing T cells in the bone marrow, we have previously found that IFNg plays an important role in the production of myeloid cells and can directly inhibit the formation of eosinophils (De Bruin et al., Blood. 2010 Jun 29). Here we demonstrate that IFNg also skews the balance between monocyte and neutrophil production in the direction of the monocytes. Increased monocyte production was also observed in WT mice infected with LCMV, which was IFNg-dependent, as it was not observed in IFNg-deficient mice. Subsequently, we set out to investigate how IFNγ can modulate the balance between monocyte and neutrophil production. We found that IFNγ reduces the proliferation and differentiation of murine hematopoietic progenitors in vitro in response to G-CSF, while M-CSF responses were not inhibited, but even slightly increased. In addition, IFNγ reduces the capacity of GMPs to form granulocyte colonies in semi-solid cultures and increases their ability to form monocyte/macrophage colonies. On a molecular level, we demonstrate that IFNγ induces a strong upregulation of SOCS3 levels and thereby reduces the phosphorylation of STAT3 in response to G-CSF, thus explaining the reduction in granulocyte formation. The expression levels of M-CSF-R and G-CSF-R by GMPs were not affected by IFNγ, but we found that IFNγ does induce the expression of the monocyte-inducing transcription factors PU.1 and IRF8 in these cells. In conclusion, these data demonstrate that IFNγ can direct myelopoiesis in a lineage-specific manner, thereby modulating the production of the appropriate type of innate immune cells required to combat infection.