Interferon-Gamma Induces Monopoiesis and Inhibits Neutrophil Development During Inflammation

Abstract 1320

Steady-state hematopoiesis is altered upon infection, but the cellular and molecular mechanisms driving these changes are largely unknown. Modulation of hematopoiesis is essential to increase the output of the appropriate type of effector cell required to combat the invading pathogen. Here we demonstrate that the pro-inflammatory cytokine interferon-gamma (IFNγ) is involved in orchestrating inflammation-induced myelopoiesis. Using both mouse models and in vitro assays we show that IFNg induces differentiation of monocytes over neutrophils at the level of myeloid progenitors. We show that acute viral infection induces monopoiesis in WT mice, but a strongly increased neutrophil production in IFNγ^−/− mice. When exploring the underlying molecular mechanism, we found that IFNγ increases expression of the monocyte-inducing transcription factors PU.1 and IRF8 in granulocyte-macrophage progenitors (GMPs) and enhances the response of these cells to M-CSF. On the contrary, IFNγ inhibits proliferation and differentiation of GMPs in response to G-CSF. We demonstrate that IFNγ reduces G-CSF-induced phosphorylation of STAT3, an important transcription factor in neutrophil development. Moreover, IFNγ also induces expression of SOCS3, which is a negative feedback regulator of G-CSFR signaling; by using G-CSFR mutants we demonstrate that the IFNγ-mediated inhibition of G-CSF-driven STAT3 phosphorylation is dependent on the recruitment of SOCS3 to the G-CSFR.

In conclusion, our findings illustrate that IFNγ is an important factor in shaping the hematopoietic response during inflammation. IFNγ is able to regulate myelopoiesis in the bone marrow upon viral infection by promoting the production of the appropriate myeloid cell type, but also by actively suppressing formation of cells less important for anti-viral defense. In addition, our data provide a molecular explanation for the observed aberrant hematopoietic remodeling observed in pathogen-challenged IFNγ-deficient mice. As both monocytes and neutrophils play important, but distinct roles in the defense against numerous pathogens, this study provides important new insight in the mechanism that regulates the formation of these vital myeloid cell types during infections.