Department of Microbiology, Immunology, and Infectious Diseases, University of Calgary, Calgary, AB, Canada.
Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada.
Front Immunol. 2020 Nov 3;11:578654. doi: 10.3389/fimmu.2020.578654. eCollection 2020.
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 reactive oxygen species (ROS) production. Therefore, we speculated that mirtazapine might adversely alter Kupffer cell pathogen-associated activation and killing.
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 .
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 -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.
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.
米氮平是一种具有 5-羟色胺和组胺受体拮抗作用的非典型抗抑郁药。临床和实验证据表明，米氮平除了治疗抑郁症外，还能改变肝脏固有免疫，抑制免疫驱动的肝巨噬细胞活化。肝巨噬细胞，即库普弗细胞，是体内最大的固定巨噬细胞群，在调节肝脏免疫中起着关键作用。除了调节炎症的能力外，库普弗细胞还是清除血源性病原体的关键哨兵，防止其在体内传播。这个过程涉及病原体捕获、吞噬和激活诱导杀伤（活性氧（ROS）的产生）。因此，我们推测米氮平可能会对库普弗细胞的病原体相关激活和杀伤产生不利影响。
通过活体显微镜观察米氮平治疗小鼠时库普弗细胞的时间依赖性变化。在静脉感染致病性菌株后，评估巨噬细胞和中性粒细胞反应、细菌播散和肝损伤。
米氮平迅速（在 1.5 小时内）激活库普弗细胞，表现为细胞变圆导致长形丧失。然而，这种形态变化并没有导致病原体捕获功能受损，实际上在细菌感染引起的败血症中产生了增强的 ROS 产生。感染后，中性粒细胞向肝脏的募集减少，导致中性粒细胞动力学发生改变。静脉给药后细菌播散未受米氮平治疗影响，但肝脓肿形成明显减少。
米氮平迅速激活库普弗细胞，与保留的细菌捕获功能和增强的 ROS 产生能力相关。此外，库普弗细胞的这些变化与肝脓肿大小的有益减少有关。与我们最初的推测相反，米氮平在败血症中可能具有有益的作用，值得进一步探索。
