The Antidepressant Mirtazapine Activates Hepatic Macrophages, Facilitating Pathogen Clearance While Limiting Tissue Damage in Mice.

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  • Additional Information
    • Source:
      Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE
    • Publication Information:
      Original Publication: [Lausanne : Frontiers Research Foundation]
    • Subject Terms:
      Antidepressive Agents/*pharmacology ; Kupffer Cells/*drug effects ; Liver/*drug effects ; Liver Abscess/*drug therapy ; Macrophage Activation/*drug effects ; Mirtazapine/*pharmacology ; Phagocytosis/*drug effects ; Staphylococcal Infections/*drug therapy ; Staphylococcus aureus/*pathogenicity; Animals ; Disease Models, Animal ; Host-Pathogen Interactions ; Kupffer Cells/metabolism ; Kupffer Cells/microbiology ; Liver/metabolism ; Liver/microbiology ; Liver/pathology ; Liver Abscess/metabolism ; Liver Abscess/microbiology ; Liver Abscess/pathology ; Mice, Inbred C57BL ; Neutrophil Infiltration/drug effects ; Neutrophils/drug effects ; Neutrophils/metabolism ; Neutrophils/microbiology ; Reactive Oxygen Species/metabolism ; Staphylococcal Infections/metabolism ; Staphylococcal Infections/microbiology ; Staphylococcal Infections/pathology ; Time Factors
    • Abstract:
      Background and Aims: Mirtazapine is an atypical antidepressant with antagonist activity for serotonin and histamine receptors. Clinical and experimental evidence suggests that, in addition to treating depression, mirtazapine also alters liver innate immunity and suppresses immune-driven hepatic macrophage activation. Liver macrophages, Kupffer cells, represent the largest collection of fixed macrophages in the body and are critical in regulating hepatic immunity. In addition to their capacity to regulate inflammation, Kupffer cells are key sentinels for clearing blood-borne pathogens, preventing their dissemination within the body. This process involves pathogen capture, phagocytosis, and activation-induced killing via reactive oxygen species (ROS) production. Therefore, we speculated that mirtazapine might adversely alter Kupffer cell pathogen-associated activation and killing.
      Methods: Mice were treated with mirtazapine and time-dependent changes in Kupffer cells were characterized using intravital microscopy. Macrophage and neutrophil responses, bacterial dissemination, and liver damage were assessed following i.v. infection with a pathogenic strain of S. aureus .
      Results: Mirtazapine rapidly (within 1.5 h) activates Kupffer cells, indicated by a loss of elongated shape with cellular rounding. However, this shape change did not result in impaired pathogen capture function, and, in fact, generated enhanced ROS production in response to S. aureus -induced sepsis. Neutrophil dynamics were altered with reduced cellular recruitment to the liver following infection. Bacterial dissemination post-intravenous administration was not altered by mirtazapine treatment; however, hepatic abscess formation was significantly reduced.
      Conclusions: Mirtazapine rapidly activates Kupffer cells, associated with preserved bacterial capture functions and enhanced ROS generation capacity. Moreover, these changes in Kupffer cells were linked to a beneficial reduction in hepatic abscess size. In contrast to our initial speculation, mirtazapine may have beneficial effects in sepsis and warrants further exploration.
      (Copyright © 2020 Davis, Almishri, Jenne and Swain.)
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    • Contributed Indexing:
      Keywords: imaging; infection; inflammation; liver; macrophage; mirtazapine
    • Accession Number:
      0 (Antidepressive Agents)
      0 (Reactive Oxygen Species)
      A051Q2099Q (Mirtazapine)
    • Publication Date:
      Date Created: 20201130 Date Completed: 20210614 Latest Revision: 20210614
    • Publication Date:
      20231215
    • Accession Number:
      PMC7673391
    • Accession Number:
      10.3389/fimmu.2020.578654
    • Accession Number:
      33250892