Toll-like receptors (TLRs) induce a multi-component inflammatory response that must be tightly regulated to avoid tissue damage. Most known regulatory mechanisms target TLR signalling pathways and thus broadly inhibit multiple aspects of the inflammatory response. Given the functional diversity of TLR-induced genes, we proposed that additional, gene-specific regulatory mechanisms exist to allow individual aspects of the TLR-induced response to be differentially regulated. Using an in vitro system of lipopolysaccharide tolerance in murine macrophages, we show that TLR-induced genes fall into two categories on the basis of their functions and regulatory requirements. We demonstrate that representatives from the two classes acquire distinct patterns of TLR-induced chromatin modifications. These gene-specific chromatin modifications are associated with transient silencing of one class of genes, which includes pro-inflammatory mediators, and priming of the second class, which includes antimicrobial effectors. These findings illustrate an adaptive response in macrophages and reveal component-specific regulation of inflammation.
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We thank S. Smale, T. Chi, M. Wan and R. Rutishauser for discussions, gifts of reagents, and technical assistance. S.L.F. is supported by the UNCF-Merck Graduate Science Research Dissertation Fellowship and by the NIH. D.C.H. is supported by the NSF and the graduate programme at Yale University. R.M. is supported by funding from the Howard Hughes Medical Institute, and the NIH.
All microarray data are available from the Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo) under accession code GSE7348.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
This file contains Supplementary Figures 1-5 and Supplementary Table 2. Supplementary Figure 1 shows pie chart representations of 50 of the top 100 genes from the class T and NT categories divided into functional groups. Supplementary Figure 2 shows more gene examples from Figure 1f, 1g, and 2b. Supplementary Figure 3 shows class NT gene induction is not due to increased mRNA stability, increased sensitivity to LPS, or positive feedback of secreted factors. Supplementary Figure 4 shows class T and NT genes are induced by the same signaling pathways in naive and tolerant macrophages, despite reduced signalling in tolerant macrophages. Supplementary Figure 5 shows reversal of suppression of class T genes following TSA, Pargyline, or DRB treatment is not due to changes in signalling in tolerant macrophages. Supplementary Table 2 shows individual gene names listed for genes represented in the pie charts in Supplementary Figure 1. (PDF 1557 kb)
This file contains Supplementary Table 1. The table contains expression data for genes differentially regulated in naïve and tolerant macrophages stimulated with LPS. Microarray analysis and gene selection was performed as described in Supplementary Methods. a) Class T genes. b) Class NT genes. (XLS 141 kb)
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Foster, S., Hargreaves, D. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007). https://doi.org/10.1038/nature05836
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