State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Sichuan 610041, People's Republic of China;
Department of Respiratory Medicine, West China Hospital, Sichuan University, Sichuan 610041, People's Republic of China;
J Immunol. 2014 Aug 1;193(3):1080-9. doi: 10.4049/jimmunol.1303218. Epub 2014 Jun 25.
Ammonia levels are often elevated in patients with cirrhosis or tumors. Patients with these diseases are immunocompromised. In this study, we investigated the effects of ammonia on a member of the immune cell family, the dendritic cells (DCs). Our results demonstrated that ammonia diminished cell count, phagocytosis, and lymphocyte stimulation of DCs. Ammonia also induced DC swelling, excessive reactive oxygen species production, and mitochondrial damage, which may constitute the underlying mechanism of ammonia-induced DC dysfunction. In ammonium chloride (NH4Cl)-loaded mice, DCs exhibited lowered phagocytosis and a weakened immune response to the chicken OVA vaccine. DCs from patients with cirrhosis or ammonia-treated healthy human blood both exhibited diminished phagocytosis. Moreover, tumor cell conditioned medium drove DCs into dysfunction, which could be reversed by ammonia elimination. In a murine colon carcinoma model, we found that ammonia could regulate tumor growth involving DCs and their related immune response. These findings reveal that ammonia could drive DCs into dysfunction, which contributes to the immunocompromised state of patients with cirrhosis or tumors.
氨水平在肝硬化或肿瘤患者中常常升高。这些疾病的患者免疫功能低下。在这项研究中，我们研究了氨对免疫细胞家族成员树突状细胞 (DCs) 的影响。我们的结果表明，氨会减少 DC 的细胞计数、吞噬作用和淋巴细胞刺激。氨还会诱导 DC 肿胀、过度产生活性氧物质和线粒体损伤，这可能构成氨诱导的 DC 功能障碍的潜在机制。在氯化铵 (NH4Cl) 负荷的小鼠中，DC 的吞噬作用降低，对鸡卵清蛋白疫苗的免疫反应减弱。肝硬化患者或氨处理的健康人血液中的 DC 均表现出吞噬作用减弱。此外，肿瘤细胞条件培养基可导致 DC 功能障碍，而氨的消除可逆转这种功能障碍。在小鼠结肠癌细胞模型中，我们发现氨可调节涉及 DC 及其相关免疫反应的肿瘤生长。这些发现表明，氨可导致 DC 功能障碍，从而导致肝硬化或肿瘤患者的免疫功能低下。
