title: Bacterial Stimulation of Toll-Like Receptor 4 Drives Macrophages To Hemophagocytose.
abstract: During acute infection with bacteria, viruses or parasites, a fraction of macrophages engulf large numbers of red and white blood cells, a process called hemophagocytosis. Hemophagocytes persist into the chronic stage of infection and have an anti-inflammatory phenotype. Salmonella enterica serovar Typhimurium infection of immunocompetent mice results in acute followed by chronic infection, with the accumulation of hemophagocytes. The mechanism(s) that triggers a macrophage to become hemophagocytic is unknown, but it has been reported that the proinflammatory cytokine gamma interferon (IFN-γ) is responsible. We show that primary macrophages become hemophagocytic in the absence or presence of IFN-γ upon infection with Gram-negative bacterial pathogens or prolonged exposure to heat-killed Salmonella enterica, the Gram-positive bacterium Bacillus subtilis, or Mycobacterium marinum. Moreover, conserved microbe-associated molecular patterns are sufficient to stimulate macrophages to hemophagocytose. Purified bacterial lipopolysaccharide (LPS) induced hemophagocytosis in resting and IFN-γ-pretreated macrophages, whereas lipoteichoic acid and synthetic unmethylated deoxycytidine-deoxyguanosine dinucleotides, which mimic bacterial DNA, induced hemophagocytosis only in IFN-γ-pretreated macrophages. Chemical inhibition or genetic deletion of Toll-like receptor 4, a pattern recognition receptor responsive to LPS, prevented both Salmonella- and LPS-stimulated hemophagocytosis. Inhibition of NF-κB also prevented hemophagocytosis. These results indicate that recognition of microbial products by Toll-like receptors stimulates hemophagocytosis, a novel outcome of prolonged Toll-like receptor signaling, suggesting hemophagocytosis is a highly conserved innate immune response.
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado-Boulder, Boulder, Colorado, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: McDonald
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado-Boulder, Boulder, Colorado, USA.
authors.forename: M Carolina
authors.initials: MC
authors.lastname: Pilonieta
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado-Boulder, Boulder, Colorado, USA.
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Nick
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado-Boulder, Boulder, Colorado, USA detweile@colorado.edu.
authors.forename: Corrella S
authors.initials: CS
authors.lastname: Detweiler
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001412:Bacillus subtilis / Q000276:immunology; D002460:Cell Line; D004912:Erythrocytes / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D019910:Mycobacterium marinum / Q000276:immunology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010587:Phagocytosis / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology*; D013682:Teichoic Acids / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000276:immunology
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D013682:Teichoic Acids; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; C009900:lipoteichoic acid; D007371:Interferon-gamma