Silica-Triggered Autoimmunity in Lupus-Prone Mice Blocked by Docosahexaenoic Acid Consumption.
Silica-Triggered Autoimmunity in Lupus-Prone Mice Blocked by Docosahexaenoic Acid Consumption.
复制标题
DOI：
10.1371/journal.pone.0160622
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Pestka JJ
中科院分区：
文献类型：
--
作者：
Bates MA;Brandenberger C;Langohr II;Kumagai K;Lock AL;Harkema JR;Holian A;Pestka JJ
职业性暴露于可吸入结晶二氧化硅（cSiO2，石英）与系统性红斑狼疮（狼疮）和其他人类自身免疫性疾病（ADs）在病因学上有关。在雌性NZBWF1小鼠（一种广泛使用的动物模型，遗传上容易发生狼疮）中，短期重复鼻内暴露于cSiO2会触发肺部和肾脏过早启动自身免疫反应。与cSiO2的触发作用相反，ω-3多不饱和脂肪酸二十二碳六烯酸（DHA）的消耗可以防止该小鼠品系自发发生自身免疫。本研究的目的是验证DHA摄入可以预防csio2引发的雌性NZBWF1小鼠自身免疫的假设。6周龄小鼠分别饲喂含有0.0、0.4、1.2或2.4% DHA的等热量AIN-93G饲粮。开始喂养2周后，小鼠每周1次鼻内灌注1 mg cSiO2，持续4周，并在实验饮食中再维持12周。然后处死小鼠，评估其肺、血液和肾脏的炎症和自身免疫标志物。DHA以浓度依赖性的方式从饮食中进入肺、红细胞和肾脏。膳食DHA剂量依赖性抑制csio2引发的肺血管周围白细胞浸润和异位淋巴组织新生。DHA消耗同时抑制csio2驱动的支气管肺泡灌洗液和血浆中促炎细胞因子、b细胞增殖因子、IgG和抗dsdna Ig的升高。DHA的预防作用进一步反映在csio2处理小鼠的蛋白尿和肾小球肾炎减少中。综上所述，DHA摄入可抑制cSiO2在雌性NZBWF1小鼠肺、血液和肾脏中引发自身免疫。我们的研究结果为饮食调节脂质组如何用于预防或延迟cSiO2触发AD提供了新的见解。这些知识为开发实用、低成本的预防策略提供了可能性，以降低暴露于csio2的个体引发AD和随后燃烧的风险。该模型需要进一步的研究来确定DHA抑制csio2诱导的自身免疫的机制，并确定预测csio2引发AD易感性的独特脂质组特征。
Occupational exposure to respirable crystalline silica (cSiO2, quartz) is etiologically linked to systemic lupus erythematosus (lupus) and other human autoimmune diseases (ADs). In the female NZBWF1 mouse, a widely used animal model that is genetically prone to lupus, short-term repeated intranasal exposure to cSiO2 triggers premature initiation of autoimmune responses in the lungs and kidneys. In contrast to cSiO2’s triggering action, consumption of the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) prevents spontaneous onset of autoimmunity in this mouse strain. The aim of this study was to test the hypothesis that consumption of DHA will prevent cSiO2-triggered autoimmunity in the female NZBWF1 mouse. Mice (6 wk old) were fed isocaloric AIN-93G diets containing 0.0, 0.4, 1.2 or 2.4% DHA. Two wk after initiating feeding, mice were intranasally instilled with 1 mg cSiO2 once per wk for 4 wk and maintained on experimental diets for an additional 12 wk. Mice were then sacrificed and the lung, blood and kidney assessed for markers of inflammation and autoimmunity. DHA was incorporated into lung, red blood cells and kidney from diet in a concentration-dependent fashion. Dietary DHA dose-dependently suppressed cSiO2-triggered perivascular leukocyte infiltration and ectopic lymphoid tissue neogenesis in the lung. DHA consumption concurrently inhibited cSiO2–driven elevation of proinflammatory cytokines, B-cell proliferation factors, IgG and anti-dsDNA Ig in both bronchoalveolar lavage fluid and plasma. DHA’s prophylactic effects were further mirrored in reduced proteinuria and glomerulonephritis in cSiO2-treated mice. Taken together, these results reveal that DHA consumption suppresses cSiO2 triggering of autoimmunity in female NZBWF1 mice as manifested in the lung, blood and kidney. Our findings provide novel insight into how dietary modulation of the lipidome might be used to prevent or delay triggering of AD by cSiO2. Such knowledge opens the possibility of developing practical, low-cost preventative strategies to reduce the risk of initiating AD and subsequent flaring in cSiO2-exposed individuals. Additional research in this model is required to establish the mechanisms by which DHA suppresses cSiO2-induced autoimmunity and to ascertain unique lipidome signatures predictive of susceptibility to cSiO2-triggered AD.