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J Immunol. 2015 Apr 15;194(8):3909-16. doi: 10.4049/jimmunol.1402077. Epub 2015 Mar 6.

IFN-γ priming of macrophages represses a part of the inflammatory program and attenuates neutrophil recruitment.

Author information

1
Experimental Vascular Biology Laboratory, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
2
Center for Experimental Molecular Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; Center for Infection and Immunity, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
3
Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; and.
4
Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, UM2, 13288 Marseille, France.
5
Experimental Vascular Biology Laboratory, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; m.dewinther@amc.uva.nl.

Abstract

Macrophages form a heterogeneous population of immune cells, which is critical for both the initiation and resolution of inflammation. They can be skewed to a proinflammatory subtype by the Th1 cytokine IFN-γ and further activated with TLR triggers, such as LPS. In this work, we investigated the effects of IFN-γ priming on LPS-induced gene expression in primary mouse macrophages. Surprisingly, we found that IFN-γ priming represses a subset of LPS-induced genes, particularly genes involved in cellular movement and leukocyte recruitment. We found STAT1-binding motifs enriched in the promoters of these repressed genes. Furthermore, in the absence of STAT1, affected genes are derepressed. We also observed epigenetic remodeling by IFN-γ priming on enhancer or promoter sites of repressed genes, which resulted in less NF-κB p65 recruitment to these sites without effects on global NF-κB activation. Finally, the epigenetic and transcriptional changes induced by IFN-γ priming reduce neutrophil recruitment in vitro and in vivo. Our data show that IFN-γ priming changes the inflammatory repertoire of macrophages, leading to a change in neutrophil recruitment to inflammatory sites.

PMID:
25750432
DOI:
10.4049/jimmunol.1402077
[Indexed for MEDLINE]
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