Division of Immunology and Division of Gastroenterology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA, USA.
Nat Immunol. 2020 Jan;21(1):42-53. doi: 10.1038/s41590-019-0539-2. Epub 2019 Nov 25.
Pathogen-associated molecular patterns (PAMPs) have the capacity to couple inflammatory gene expression to changes in macrophage metabolism, both of which influence subsequent inflammatory activities. Similar to their microbial counterparts, several self-encoded damage-associated molecular patterns (DAMPs) induce inflammatory gene expression. However, whether this symmetry in host responses between PAMPs and DAMPs extends to metabolic shifts is unclear. Here, we report that the self-encoded oxidized phospholipid oxPAPC alters the metabolism of macrophages exposed to lipopolysaccharide. While cells activated by lipopolysaccharide rely exclusively on glycolysis, macrophages exposed to oxPAPC also use mitochondrial respiration, feed the Krebs cycle with glutamine, and favor the accumulation of oxaloacetate in the cytoplasm. This metabolite potentiates interleukin-1β production, resulting in hyperinflammation. Similar metabolic adaptions occur in vivo in hypercholesterolemic mice and human subjects. Drugs that interfere with oxPAPC-driven metabolic changes reduce atherosclerotic plaque formation in mice, thereby underscoring the importance of DAMP-mediated activities in pathophysiological conditions.
病原体相关分子模式（PAMPs）有能力将炎症基因表达与巨噬细胞代谢变化联系起来，这两者都会影响随后的炎症活动。类似于它们的微生物对应物，几种自我编码的损伤相关分子模式（DAMPs）诱导炎症基因表达。然而，PAMPs 和 DAMPs 之间的宿主反应是否存在这种对称性延伸到代谢变化尚不清楚。在这里，我们报告自我编码的氧化磷脂 oxPAPC 改变了暴露于脂多糖的巨噬细胞的代谢。虽然被脂多糖激活的细胞完全依赖糖酵解，但暴露于 oxPAPC 的巨噬细胞也使用线粒体呼吸，用谷氨酰胺为三羧酸循环提供燃料，并有利于细胞质中草酰乙酸的积累。这种代谢物增强了白细胞介素-1β的产生，导致过度炎症。在高胆固醇血症小鼠和人类受试者的体内也发生了类似的代谢适应。干扰 oxPAPC 驱动的代谢变化的药物可减少小鼠动脉粥样硬化斑块的形成，从而强调了 DAMP 介导的活性在病理生理条件下的重要性。
