Journal Article

IFNγ shapes macrophage inflammatory responses by STAT1 isoform-specific epigenetic and transcriptional mechanisms

Halbritter, Florian, Akagha, Mojoyinola Joanna, Strobl, Birgit, Georgolopoulos, Grigorios, Martin, David, Vogl, Claus, Meissl, Katrin, Müller, Mathias, Decker, Thomas, Amenitsch, Lena, Fortelny, Nikolaus, Farlik, Matthias

2026

Overview

Background Interferon-γ (IFNγ) is a key cytokine that activates macrophages and is essential for the defence against intracellular pathogens. Beyond its immediate effects, IFNγ also shapes macrophages for subsequent encounters with pathogen-associated molecules by multiple mechanisms, including chromatin remodelling. Here, we employed integrated epigenomic and transcriptomic approaches utilizing primary macrophages from gene-modified mice to explore the role of STAT1 and its naturally occurring isoforms in these processes. Results Using ChIP-seq for histone modifications (H3K27ac and H3K4me1) and RNA-seq, we demonstrate that STAT1 isoforms differentially modulate macrophage responses to lipopolysaccharide (LPS) following IFNγ conditioning. We provide genetic evidence that STAT1 isoforms exhibit distinct capacities to mediated IFNγ-induced changes in H3K27 acetylation at promoter and enhancer regions, thereby shaping transcriptional responses to LPS. We show that the STAT1β isoform, which lacks the C-terminal transactivation domain (TAD), is unable to mediate the repressive effect of IFNγ on transcriptional regulation by LPS but retains significant collaborative activity. Furthermore, we show that IFNγ attenuates the induction of a subset of antiviral genes and represses LPS-induced negative feedback loops, thereby amplifying the inflammatory response to pathogens. These effects are dependent on the presence of the STAT1 C-terminal TAD, highlighting its importance in fine-tuning the balance between inflammatory and antiviral responses. Conclusions Our findings uncover isoform-specific roles of STAT1 in IFNγ-driven epigenetic regulation and macrophage conditioning, providing new insights into the control of inflammation and innate immunity.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Acetylation / Animal Genetics and Genomics / Animals / Biomedical and Life Sciences / Bone marrow / Chromatin remodeling / Conditioning / Control theory / Cytokines / Epigenesis, Genetic / Epigenetics / Feedback loops / Gene expression / Gene Expression Regulation / Gene regulation / Genomes / H3K27ac / H3K4me1 / Histones / Histones - metabolism / Inflammation / Inflammation - genetics / Inflammatory response / Innate immunity / Interferon- γ / Interferon-gamma - metabolism / Interferon-gamma - pharmacology / Isoforms / Kinases / Life Sciences / Lipopolysaccharide (LPS) / Lipopolysaccharides / Lipopolysaccharides - pharmacology / Macrophage conditioning / Macrophages / Macrophages - drug effects / Macrophages - immunology / Macrophages - metabolism / Mice / Microarrays / Microbial Genetics and Genomics / Negative feedback / Pathogens / Plant Genetics and Genomics / Protein Isoforms - genetics / Protein Isoforms - metabolism / Proteomics / RNA polymerase / RNA-seq / Stat1 protein / STAT1 Transcription Factor - chemistry / STAT1 Transcription Factor - genetics / STAT1 Transcription Factor - metabolism / Statistical analysis / Transcription factors / Transcription, Genetic / Transcriptomics / γ-Interferon