The yin and yang of cytokine priming on the macrophage epigenome

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Science Immunology  03 Nov 2017:
Vol. 2, Issue 17, eaaq0016
DOI: 10.1126/sciimmunol.aaq0016


TNF and type I interferons alter TLR4 responses by reprogramming the macrophage genome.

Cytokines influence macrophage inflammatory responses; however, specific mechanisms involved remain unknown. Cytokine exposure has a broad impact on immune responses to infections and autoimmune diseases. Type I interferons (IFN-I) enhance antiviral activity and systemic lupus erythematosus (SLE) disease activity, whereas IFN-I ameliorate multiple sclerosis. Tumor necrosis factor (TNF) antagonizes the effects of IFN-I in SLE and promotes inflammation in rheumatoid arthritis (RA) and Crohn’s disease.

The article by Park et al. describes how TNF and IFN-I alter Toll-like receptor 4 (TLR4) responses by reprogramming the macrophage epigenome. These studies assessed the effects of pretreatment with TNF on lipopolysaccharide (LPS)–stimulated human macrophages and examined chromatin remodeling and gene expression by RNA-sequencing, chromatin immunoprecipitation sequencing, and assay for transposase-accessible chromatin sequencing. TNF pretreatment of macrophages altered gene expression responses, which were categorized into six groups. TNF induced “cross-tolerance” of nuclear factor κB (NFκB)-induced and inflammatory groups, the IFN-I group was nontolerized, whereas LPS and TNF synergized to induce the small molecule-lipid-metabolic group.

TNF-induced tolerance substantially blocked TLR4-induced gene expression. Histone marks and promoter/enhancer studies suggested that TNF altered chromatin to suppress gene expression of NFκB-induced and inflammatory groups. TNF tolerance differed from endotoxin tolerance as there was no inhibition of the IFN-I and small molecule-lipid-metabolic groups.

LPS-induced transcripts were analyzed in monocytes collected from patients with sepsis and after recovery. Patient monocyte transcriptional profile patterns were similar to TNF tolerance-induced profiles, which were reversed after patient recovery. Consistent with these effects, RA synovial macrophages expressed elevated levels of transcripts from nontolerized genes.

IFN-I added together with TNF restored expression of several LPS-inducible genes but did not reverse tolerization of TNF and IL6 genes. IFN-I did not affect TLR4 proximal signaling events, including expression of noncanonical NFκB molecules, suggesting a role for IFN-I downstream, in the nucleus. IFN-I pretreatment inhibited interleukin-10-mediated suppression of LPS-induced IL6 and related genes. Gene expression of ex vivo LPS-stimulated SLE monocytes correlated with that observed in IFN-I–treated TNF-tolerized monocytes.

In summary IFN-1 prime chromatin to facilitate vigorous transcriptional responses to weak stimulation and prevent TNF cross-tolerance. These studies elucidate cytokine-mediated mechanisms that integrate with TLR4 signaling to alter the epigenome and result in the functional reprogramming of macrophage inflammatory gene expression.

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