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Updated: Jul 1, 2026
Depletion and Reconstitution of Macrophages in Mice
Published on: August 1, 2012
The Antidepressant Mirtazapine Activates Hepatic Macrophages, Facilitating Pathogen Clearance While Limiting Tissue
Rachelle Paige Davis1,2, Wagdi Almishri1,2, Craig Neal Jenne1,2
1Department of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, AB, Canada.
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.
Insights
Mirtazapine rapidly activates Kupffer cells, enhancing pathogen killing and reducing liver abscesses in mice. This antidepressant may offer unexpected benefits in sepsis treatment.
Area of Science:
- Immunology
- Pharmacology
- Hepatology
Background:
- Mirtazapine, an atypical antidepressant, modulates serotonin and histamine receptors.
- Evidence suggests mirtazapine impacts liver innate immunity, specifically Kupffer cell activation.
- Kupffer cells are crucial for hepatic immunity, pathogen clearance, and inflammation regulation.
Purpose of the Study:
- To investigate the effect of mirtazapine on Kupffer cell function and host defense against bacterial infection.
- To determine if mirtazapine alters Kupffer cell pathogen-associated activation and killing capacity.
Main Methods:
- Mice were administered mirtazapine, and Kupffer cell dynamics were observed using intravital microscopy.
- Macrophage and neutrophil responses, bacterial spread, and liver injury were evaluated after *S. aureus* infection.
Main Results:
- Mirtazapine rapidly activated Kupffer cells, characterized by cellular rounding within 1.5 hours.
- Despite shape changes, pathogen capture remained intact, and reactive oxygen species (ROS) production increased upon *S. aureus* challenge.
- Neutrophil recruitment to the liver was reduced, bacterial dissemination was unchanged, but hepatic abscess formation significantly decreased.
Conclusions:
- Mirtazapine enhances Kupffer cell activation, preserves bacterial capture, and boosts ROS generation.
- These mirtazapine-induced Kupffer cell alterations correlate with reduced hepatic abscesses.
- Mirtazapine demonstrates potential beneficial effects in sepsis, meriting further investigation.
