Abstract
Background and AimsMirtazapine 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.MethodsMice 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.ResultsMirtazapine 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.ConclusionsMirtazapine 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.
Highlights
Depression is common in society, with a global lifetime prevalence of up to 15% and significant associated disability [1, 2]
Previous work has shown that peak neutrophil recruitment to the liver occurs 4 h after bacterial infection and these neutrophils provide a scaffold facilitating platelet aggregation leading to the production of neutrophil extracellular traps (NETs) [26]
When NET production is normalized to the number of neutrophils in the liver, it becomes apparent that mirtazapine-treatment leads to enhanced NET production on a per-neutrophil basis following S. aureus infection (Figure 3Ciii)
Summary
Depression is common in society, with a global lifetime prevalence of up to 15% and significant associated disability [1, 2]. The use of antidepressants is common among patients with comorbid medical conditions [7] and interestingly, antidepressant therapy may improve clinical outcomes in these patients [8,9,10] Despite these clinical observations there is limited understanding of the impact of antidepressants on immunity. Mirtazapine exhibits promiscuous receptor engagement, including antagonistic effects at a2-adrenoreceptors and 5-HT2 and HT3 receptors [11] These receptors are enriched in the liver, especially on macrophages [12]. 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. We speculated that mirtazapine might adversely alter Kupffer cell pathogen-associated activation and killing
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
