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Sci Signal. 2019 May 14;12(581). pii: eaao5820. doi: 10.1126/scisignal.aao5820.

Signals trigger state-specific transcriptional programs to support diversity and homeostasis in immune cells.

Fischer C1,2,3, Metsger M1,2,3,4, Bauch S1,2, Vidal R1, Böttcher M2, Grote P2,5, Kliem M1,2, Sauer S6,2,7.

Author information

1
Laboratory of Functional Genomics, Nutrigenomics and Systems Biology, Scientific Genomics Platforms, Max Delbrück Center for Molecular Medicine (BIMSB/BIH), 13092 Berlin, Germany.
2
Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
3
Department of Biology, Chemistry, and Pharmacy, Free University of Berlin, 14195 Berlin, Germany.
4
Central European Institute of Technology, Masaryk University, 62500 Brno, Czech Republic.
5
Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University, 60590 Frankfurt am Main, Germany.
6
Laboratory of Functional Genomics, Nutrigenomics and Systems Biology, Scientific Genomics Platforms, Max Delbrück Center for Molecular Medicine (BIMSB/BIH), 13092 Berlin, Germany. sascha.sauer@mdc-berlin.de.
7
CU Systems Medicine, University of Würzburg, 97080 Würzburg, Germany.

Abstract

Macrophages play key roles in the immune systems of humans and other mammals. Here, we performed single-cell analyses of the mRNAs and proteins of human macrophages to compare their responses to the signaling molecules lipopolysaccharide (LPS), a component of Gram-negative bacteria, and palmitate (PAL), a free fatty acid. We found that, although both molecules signal through the cell surface protein Toll-like receptor 4 (TLR4), they stimulated the expression of different genes, resulting in specific pro- and anti-inflammatory cellular states for each signal. The effects of the glucocorticoid receptor, which antagonizes LPS signaling, and cyclic AMP-dependent transcription factor 3, which inhibits PAL-induced inflammation, on inflammatory response seemed largely determined by digital on-off events. Furthermore, the quantification of transcriptional variance and signaling entropy enabled the identification of cell state-specific deregulated molecular pathways. These data suggest that the preservation of signaling in distinct cells might confer diversity on macrophage populations essential to maintaining major cellular functions.

PMID:
31088978
DOI:
10.1126/scisignal.aao5820

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