Liver Unit, Snyder Institute for Chronic Disease, University of Calgary, Calgary, AB, Canada.
Cumming School of Medicine, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.
Front Immunol. 2019 Apr 12;10:803. doi: 10.3389/fimmu.2019.00803. eCollection 2019.
Activation of the innate immune system, including tissue macrophages and associated neutrophil infiltration, is an important driver of subsequent adaptive immune responses in many autoimmune diseases, including autoimmune hepatitis (AIH). The antidepressant mirtazapine has a unique complex pharmacology, altering signaling through a number of serotonin and histamine receptors that can impact macrophage function; an effect potentially influencing AIH outcome. In the mouse model of concanavalin A (Con A) induced liver injury (mimics many aspects of human AIH), in which early innate immune activation (i.e., stimulated hepatic macrophages/monocytes recruit neutrophils and additional monocytes to the liver) critically drives immune-mediated hepatitis induction, mirtazapine strikingly and dose-dependently inhibited Con A-induced liver injury. This inflammation-suppressing effect of mirtazapine was linked to an attenuation of Con A-stimulated early innate immune responses within the liver, including inhibition of hepatic macrophage/monocyte activation, decreased hepatic macrophage/monocyte-derived pro-inflammatory cytokine (e.g., TNFα) and chemokine (e.g., CXCL1 and CXCL2) production, suppression of Con A-induced increases in the hepatic expression of the neutrophil relevant endothelial cell adhesion molecule ICAM-1, with the resultant significant reduction in neutrophil recruitment into the liver. Consistent with our findings in the Con A model, mirtazapine also significantly reduced activation-induced release of cytokine/chemokine mediators from human CD14 monocytes . Our data suggest that mirtazapine can attenuate hepatic innate immune responses that critically regulate the subsequent development of autoimmune liver injury. Therefore, given that it is a safe and widely used medication, mirtazapine may represent a novel therapeutic approach to autoimmune liver disease.
固有免疫系统的激活，包括组织巨噬细胞和相关中性粒细胞浸润，是许多自身免疫性疾病（包括自身免疫性肝炎（AIH））随后适应性免疫反应的重要驱动因素。抗抑郁药米氮平具有独特的复杂药理学，通过改变许多 5-羟色胺和组胺受体的信号传导，从而影响巨噬细胞功能；这种影响可能会影响 AIH 的结果。在伴刀豆球蛋白 A（Con A）诱导的肝损伤小鼠模型中（模拟了许多人类 AIH 的方面），早期固有免疫激活（即，刺激肝巨噬细胞/单核细胞招募中性粒细胞和其他单核细胞进入肝脏）严重驱动免疫介导的肝炎诱导，米氮平显着且剂量依赖性地抑制了 Con A 诱导的肝损伤。米氮平的这种抗炎作用与 Con A 刺激的肝内早期固有免疫反应的减弱有关，包括抑制肝巨噬细胞/单核细胞的激活、减少肝巨噬细胞/单核细胞衍生的促炎细胞因子（如 TNFα）和趋化因子（如 CXCL1 和 CXCL2）的产生、抑制 Con A 诱导的肝内中性粒细胞相关内皮细胞黏附分子 ICAM-1 的表达增加，从而导致中性粒细胞向肝脏的募集显着减少。与我们在 Con A 模型中的发现一致，米氮平还显着降低了人 CD14 单核细胞中激活诱导的细胞因子/趋化因子介质的释放。我们的数据表明，米氮平可以减弱肝脏固有免疫反应，这些反应对随后发生的自身免疫性肝损伤的发展起着至关重要的作用。因此，鉴于它是一种安全且广泛使用的药物，米氮平可能代表治疗自身免疫性肝病的一种新方法。
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