IRF1 governs the differential interferon-stimulated gene responses in human monocytes and macrophages by regulating chromatin accessibility
Ran Song,
Yajing Gao,
Igor Dozmorov,
Venkat Malladi,
Irene Saha,
Margaret M. McDaniel,
Sreeja Parameswaran,
Chaoying Liang,
Carlos Arana,
Bo Zhang,
Benjamin Wakeland,
Jinchun Zhou,
Matthew T. Weirauch,
Leah C. Kottyan,
Edward K. Wakeland,
Chandrashekhar Pasare
Affiliations
Ran Song
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Yajing Gao
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Igor Dozmorov
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Venkat Malladi
Bioinformatics Core Facility, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Irene Saha
Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
Margaret M. McDaniel
Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Sreeja Parameswaran
Center for Autoimmune Genetics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
Chaoying Liang
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Carlos Arana
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Bo Zhang
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Benjamin Wakeland
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Jinchun Zhou
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Matthew T. Weirauch
Center for Autoimmune Genetics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; Divisions of Biomedical Informatics and Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Leah C. Kottyan
Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; Center for Autoimmune Genetics and Etiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
Edward K. Wakeland
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Corresponding author
Chandrashekhar Pasare
Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; Corresponding author
Summary: Myeloid lineage cells use TLRs to recognize and respond to diverse microbial ligands. Although unique transcription factors dictate the outcome of specific TLR signaling, whether lineage-specific differences exist to further modulate the quality of TLR-induced inflammation remains unclear. Comprehensive analysis of global gene transcription in human monocytes, monocyte-derived macrophages, and monocyte-derived dendritic cells stimulated with various TLR ligands identifies multiple lineage-specific, TLR-responsive gene programs. Monocytes are hyperresponsive to TLR7/8 stimulation that correlates with the higher expression of the receptors. While macrophages and monocytes express similar levels of TLR4, macrophages, but not monocytes, upregulate interferon-stimulated genes (ISGs) in response to TLR4 stimulation. We find that TLR4 signaling in macrophages uniquely engages transcription factor IRF1, which facilitates the opening of ISG loci for transcription. This study provides a critical mechanistic basis for lineage-specific TLR responses and uncovers IRF1 as a master regulator for the ISG transcriptional program in human macrophages.
