title: Mycobacterium tuberculosis- induced neutrophil extracellular traps activate human macrophages.
abstract: Neutrophils activated by Mycobacterium tuberculosis (Mtb) form neutrophil extracellular traps (NETs), containing DNA and several biologically active cytosolic and granular proteins. These NETs may assist in the innate immune defense against different pathogens. We investigated whether the NET-forming neutrophils mediate an activating signal to macrophages during the early multicellular inflammatory reaction and granuloma formation. Mtb-induced NETs were found to be reactive oxygen species dependent and phagocytosis dependent. A neutrophil elastase inhibitor also delayed NET formation. However, NET formation occurred independently of Mtb-induced apoptosis. We observed close interactions between macrophages and Mtb-activated neutrophils, where macrophages bound and phagocytosed NETs. Significant secretion of the cytokines interleukin (IL)-6, tumor necrosis factor-α, IL-1β and IL-10 were detected from macrophages cocultured with NETs from Mtb-activated but not phorbol myristate acetate-activated neutrophils. NETs binding heat shock protein 72 (Hsp72) or recombinant Hsp72 were able to trigger cytokine release from macrophages. Only Mtb-induced NETs contained Hsp72, suggesting that these NETs can transfer this danger signal to adjacent macrophages. We propose that Hsp72 sequestered in NETs plays an important role in the interaction between neutrophils and macrophages during the early innate immune phase of an Mtb infection. The immunomodulatory role of NETs and proteins derived from them may influence not only chronic inflammation during tuberculosis but also immune regulation and autoimmunity.
authors: Division of Medical Microbiology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors: Clara
authors: C
authors: Braian
authors: Valentin
authors: V
authors: Hogea
authors: Olle
authors: O
authors: Stendahl
mesh_terms: D002478:Cells, Cultured; D018920:Coculture Techniques; D050884:HSP72 Heat-Shock Proteins / Q000276:immunology / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D007700:Kinetics; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008856:Microscopy, Fluorescence; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000502:physiology; D018375:Neutrophil Activation / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D010587:Phagocytosis / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000276:immunology / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D050884:HSP72 Heat-Shock Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D013755:Tetradecanoylphorbol Acetate
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