IFNγ is a cytokine with important roles in tissue homeostasis, immune and inflammatory responses and tumour immunosurveillance. Signalling by the IFNγ receptor activates the Janus kinase (JAK)–signal transducer and activator of transcription 1 (STAT1) pathway to induce the expression of classical interferon-stimulated genes that have key immune effector functions. This Review focuses on recent advances in our understanding of the transcriptional, chromatin-based and metabolic mechanisms that underlie IFNγ-mediated polarization of macrophages to an ‘M1-like’ state, which is characterized by increased pro-inflammatory activity and macrophage resistance to tolerogenic and anti-inflammatory factors. In addition, I describe the newly discovered effects of IFNγ on other leukocytes, vascular cells, adipose tissue cells, neurons and tumour cells that have important implications for autoimmunity, metabolic diseases, atherosclerosis, neurological diseases and immune checkpoint blockade cancer therapy.
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This work was supported by grants from the National Institutes of Health.
Nature Reviews Immunology thanks T. Decker, G. Trinchieri and P. Hertzog for their assistance with the peer review of this manuscript.
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- IFNγ signature
A pattern of elevated expression of canonical IFNγ target genes in inflamed tissues; it is often detected in samples from patients with autoimmune disease.
- Endotoxin tolerance
Classically, a macrophage cell state in which prior exposure to lipopolysaccharide (LPS; an endotoxin) renders inflammatory nuclear factor-κB (NF-κB) target genes refractory to induction by subsequent LPS challenge. Tolerance can be induced by various inflammatory factors such as tumour necrosis factor (TNF), IL-1 and Toll-like receptor (TLR) ligands, and tolerized cells are resistant to multiple cell activators.
- Interferon-stimulated gene factor 3
(ISGF3). A transcription factor complex comprising signal transducer and activator of transcription 1 (STAT1), STAT2 and interferon regulatory factor 9 (IRF9) that binds to interferon-stimulated response elements and regulates the expression of interferon-stimulated genes. ISGF3 is predominantly activated by type I interferons.
- Latent enhancers
Enhancers that are inactive and associated with closed chromatin in resting myeloid cells. During cell activation, chromatin at latent enhancers becomes accessible, and they bind to transcription factors and drive expression of associated genes.
- M2 macrophage
A type of macrophage that has been polarized by IL-4, IL-13, IL-10, glucocorticoids or various anti-inflammatory factors. M2 macrophages exhibit a range of phenotypes related to resolution of inflammation, wound healing and tissue remodelling.
The selective degradation of mitochondria by autophagy.
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Ivashkiv, L.B. IFNγ: signalling, epigenetics and roles in immunity, metabolism, disease and cancer immunotherapy. Nat Rev Immunol 18, 545–558 (2018). https://doi.org/10.1038/s41577-018-0029-z
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