IFNγ induces monopoiesis and inhibits neutrophil development during inflammation

• Published in: Blood 2012-02, Vol.119 (6), p.1543-1554
• Main Authors: de Bruin, Alexander M., Libregts, Sten F., Valkhof, Marijke, Boon, Louis, Touw, Ivo P., Nolte, Martijn A.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Bone Marrow Cells - immunology; Bone Marrow Cells - metabolism; CD27 Ligand - genetics; CD27 Ligand - metabolism; Cell Differentiation - drug effects; Cells, Cultured; Granulocyte Colony-Stimulating Factor - pharmacology; Hematologic and hematopoietic diseases; Inflammation - genetics; Inflammation - metabolism; Inflammation Mediators - metabolism; Inflammation Mediators - pharmacology; Inflammation Mediators - physiology; Interferon Regulatory Factors - metabolism; Interferon-gamma - genetics; Interferon-gamma - pharmacology; Interferon-gamma - physiology; Lymphocytic Choriomeningitis - genetics; Lymphocytic Choriomeningitis - immunology; Lymphocytic Choriomeningitis - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Monocytes - cytology; Monocytes - metabolism; Myeloid Progenitor Cells - metabolism; Myelopoiesis - drug effects; Neutrophils - cytology; Neutrophils - metabolism; Phosphorylation; Proto-Oncogene Proteins - metabolism; STAT3 Transcription Factor - metabolism; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Trans-Activators - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-07-367706

Steady-state hematopoiesis is altered on 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. In the present study, we demonstrate that the pro-inflammatory cytokine IFNγ is involved in orchestrating inflammation-induced myelopoiesis. Using both mouse models and in vitro assays, we show that IFNγ induces the differentiation of monocytes over neutrophils at the level of myeloid progenitors. Infection with lymphocytic choriomeningitis virus induces monopoiesis in wild-type mice, but causes increased neutrophil production in IFNγ−/− mice. We demonstrate that IFNγ enhances the expression of the monopoiesis-inducing transcription factors IRF8 and PU.1 in myeloid progenitor cells, whereas it reduces G-CSF–driven neutrophil differentiation via a SOCS3-dependent inhibition of STAT3 phosphorylation. These results establish a critical role for IFNγ in directing monocyte versus neutrophil development during immune activation.