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.

Laboratory of Functional Genomics Nutrigenomics and Systems Biology Scientific Genomics Platforms Max Delbrück Center for Molecular Medicine 13092 Berlin Germany

Laboratory of Functional Genomics Nutrigenomics and Systems Biology Scientific Genomics Platforms Max Delbrück Center for Molecular Medicine 13092 Berlin Germany Max Planck Institute for Molecular Genetics 14195 Berlin Germany

Laboratory of Functional Genomics Nutrigenomics and Systems Biology Scientific Genomics Platforms Max Delbrück Center for Molecular Medicine 13092 Berlin Germany Max Planck Institute for Molecular Genetics 14195 Berlin Germany CU Systems Medicine University of Würzburg 97080 Würzburg Germany

Laboratory of Functional Genomics Nutrigenomics and Systems Biology Scientific Genomics Platforms Max Delbrück Center for Molecular Medicine 13092 Berlin Germany Max Planck Institute for Molecular Genetics 14195 Berlin Germany Department of Biology Chemistry and Pharmacy Free University of Berlin 14195 Berlin Germany

Laboratory of Functional Genomics Nutrigenomics and Systems Biology Scientific Genomics Platforms Max Delbrück Center for Molecular Medicine 13092 Berlin Germany Max Planck Institute for Molecular Genetics 14195 Berlin Germany Department of Biology Chemistry and Pharmacy Free University of Berlin 14195 Berlin Germany Central European Institute of Technology Masaryk University 62500 Brno Czech Republic

Max Planck Institute for Molecular Genetics 14195 Berlin Germany

Max Planck Institute for Molecular Genetics 14195 Berlin Germany Institute of Cardiovascular Regeneration Centre for Molecular Medicine Goethe University 60590 Frankfurt am Main Germany

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