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

• Published in: The Journal of immunology (1950) Vol. 194; no. 8; pp. 3909 - 3916
• Main Authors: Hoeksema, Marten A, Scicluna, Brendon P, Boshuizen, Marieke C S, van der Velden, Saskia, Neele, Annette E, Van den Bossche, Jan, Matlung, Hanke L, van den Berg, Timo K, Goossens, Pieter, de Winther, Menno P J
• Format: Journal Article
• Language: English
• Published: United States 15.04.2015
• Subjects: Animals; Cell Movement - drug effects; Cell Movement - immunology; Epigenesis, Genetic - drug effects; Epigenesis, Genetic - immunology; Female; Inflammation - immunology; Interferon-gamma - immunology; Lipopolysaccharides - pharmacology; Macrophages - immunology; Mice; Mice, Knockout; Neutrophils - immunology; Response Elements - immunology; STAT1 Transcription Factor - immunology; Toll-Like Receptors - agonists; Toll-Like Receptors - immunology; Transcription Factor RelA - immunology
• DOI: 10.4049/jimmunol.1402077
• ISSN: 0022-1767

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.