IFN-γ priming of macrophages represses a part of the inflammatory program and attenuates neutrophil recruitment.
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.
Experimental Vascular Biology Laboratory, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
Marten A
MA
Hoeksema
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;
Brendon P
BP
Scicluna
Experimental Vascular Biology Laboratory, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
Marieke C S
MC
Boshuizen
Experimental Vascular Biology Laboratory, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
Saskia
S
van der Velden
Experimental Vascular Biology Laboratory, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
Annette E
AE
Neele
Experimental Vascular Biology Laboratory, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
Jan
J
Van den Bossche
Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; and.
Hanke L
HL
Matlung
Sanquin Research and Landsteiner Laboratory, Department of Blood Cell Research, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; and.
Timo K
TK
van den Berg
Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, UM2, 13288 Marseille, France.
Pieter
P
Goossens
Experimental Vascular Biology Laboratory, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands; m.dewinther@amc.uva.nl.
Menno P J
MP
de Winther
D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000276:immunology*; D005260:Female; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D020218:Response Elements / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology; D051996:Transcription Factor RelA / Q000276:immunology
D008070:Lipopolysaccharides; C498144:Rela protein, mouse; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D007371:Interferon-gamma