The Human Milk Oligosaccharide 3’Sialyllactose Promotes Inflammation Resolution and Reduces Atherosclerosis Development in Mice

Macrophages contribute to the induction and resolution of inflammation and play a central role in the chronic low-grade inflammation in cardiovascular diseases caused by atherosclerosis. Human milk oligosaccharides (HMOs) are complex unconjugated glycans unique to human milk that benefit infant health and act as innate immune modulators. Here we identify the HMO 3’sialyllactose (3’SL) as a natural inhibitor of TLR4-induced low-grade inflammation in macrophages and endothelium. Transcriptome analysis in macrophages revealed that 3’SL attenuates a selected set of inflammatory gene expression and promotes activity of LXR and SREBP. Surprisingly, the acute anti-inflammatory effects of 3’SL were associated with reduced histone H3K27 acetylation at a subset of LPS-inducible enhancers distinguished by preferential enrichment for CTCF, IRF2, BCL6 and other transcription factor recognition motifs. In a murine atherosclerosis model, the subcutaneous administration of 3’SL significantly reduced atherosclerosis development and macrophage content in atherosclerotic lesions. This study provides evidence that 3’SL attenuates inflammation by a transcriptional mechanism to reduce atherosclerosis development in the context of cardiovascular disease. We designed four different intervention groups (PBS, HMO, LPS, and LPS+HMO), each in triplicate for a total of 12 different samples.

巨噬细胞（Macrophages）参与炎症的诱导与消退，在动脉粥样硬化引发的心血管疾病慢性低度炎症中发挥核心作用。人乳低聚糖（Human milk oligosaccharides, HMOs）是人类乳汁特有的复杂非结合型聚糖，可惠及婴儿健康并充当先天免疫调节剂。本研究鉴定出人乳低聚糖3’唾液酸乳糖（3’sialyllactose, 3’SL）是Toll样受体4（TLR4）诱导的巨噬细胞与内皮细胞低度炎症的天然抑制剂。对巨噬细胞开展的转录组分析显示，3’SL可减弱一组特定炎症基因的表达，并促进肝X受体（liver X receptor, LXR）与固醇调节元件结合蛋白（sterol regulatory element-binding protein, SREBP）的活性。令人意外的是，3’SL的急性抗炎效应与脂多糖（Lipopolysaccharide, LPS）诱导的部分增强子区域的组蛋白H3K27乙酰化水平降低相关，这类增强子以优先富集CTCF、IRF2、BCL6及其他转录因子识别基序为特征。在动脉粥样硬化小鼠模型中，皮下给予3’SL可显著抑制动脉粥样硬化病变进展，并减少病灶内的巨噬细胞含量。本研究证实，3’SL可通过转录调控机制减轻炎症，从而延缓心血管疾病背景下的动脉粥样硬化进程。本研究设置了4组不同干预方案（磷酸盐缓冲液（PBS）、HMO、LPS、LPS+HMO），每组设置3个生物学重复，总计获得12份不同样本。