Silicosis is a lethal pneumoconiosis for which no therapy is available. Silicosis is a global threat, and more than 2.2 million people per year are exposed to silica in the United States. The initial response to silica is mediated by innate immunity. Phagocytosis of silica particles by macrophages is followed by recruitment of mitochondria to phagosomes, generation of mitochondrial reactive oxygen species, and cytokine (IL-1β, TNF-α, IFN-β) release. In contrast with LPS, the metabolic remodeling of silica-exposed macrophages is unclear. This study contrasts mitochondrial and metabolic alterations induced by LPS and silica on macrophages and correlates them with macrophage viability and cytokine production, which are central to the pathogenesis of silicosis. Using high-resolution respirometer and liquid chromatography–high-resolution mass spectrometry, we determined the effects of silica and LPS on mitochondrial respiration and determined changes in central carbon metabolism of murine macrophage cell lines RAW 264.7 and IC-21. We show that silica induces metabolic reprogramming of macrophages. Silica, as well as LPS, enhances glucose uptake and increases aerobic glycolysis in macrophages. In contrast with LPS, silica affects mitochondria respiration, reducing complex I and enhancing complex II activity, to sustain cell viability. These mitochondrial alterations are associated in silica, but not in LPS-exposed macrophages, with reductions of tricarboxylic acid cycle intermediates, including succinate, itaconate, glutamate, and glutamine. Furthermore, in contrast with LPS, these silica-induced metabolic adaptations do not correlate with IL-1β or TNF-α production, but with the suppressed release of IFN-β. Our data highlight the importance of complex II activity and tricarboxylic acid cycle remodeling to macrophage survival and cytokine-mediated inflammation in silicosis.

矽肺是一种致命的尘肺病，目前尚无治疗方法。矽肺病是一种全球性威胁，在美国，每年有超过 220 万人接触二氧化硅。对二氧化硅的初始反应是由先天免疫介导的。巨噬细胞对二氧化硅颗粒的吞噬作用之后是将线粒体募集到吞噬体、线粒体活性氧的产生和细胞因子（IL-1β、TNF-α、IFN-β）的释放。与 LPS 相比，二氧化硅暴露的巨噬细胞的代谢重塑尚不清楚。该研究对比了 LPS 和二氧化硅对巨噬细胞的线粒体和代谢改变，并将它们与巨噬细胞活力和细胞因子产生相关联，这是矽肺发病机制的核心。使用高分辨率呼​​吸计和液相色谱-高分辨率质谱，我们确定了二氧化硅和 LPS 对线粒体呼吸的影响，并确定了鼠巨噬细胞系 RAW 264.7 和 IC-21 的中心碳代谢变化。我们表明二氧化硅诱导巨噬细胞的代谢重编程。二氧化硅以及 LPS 可增强巨噬细胞的葡萄糖摄取并增加有氧糖酵解。与 LPS 相比，二氧化硅影响线粒体呼吸，减少复合物 I 并增强复合物 II 活性，以维持细胞活力。这些线粒体改变与二氧化硅有关，但与 LPS 暴露的巨噬细胞无关，三羧酸循环中间体减少，包括琥珀酸、衣康酸、谷氨酸和谷氨酰胺。此外，与 LPS 相比，这些二氧化硅诱导的代谢适应与 IL-1β 或 TNF-α 的产生无关，但与 IFN-β 的抑制释放有关。我们的数据强调了复合物 II 活性和三羧酸循环重塑对矽肺中巨噬细胞存活和细胞因子介导的炎症的重要性。